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Inducible, Site-Specific Protein Labeling by Tyrosine Oxidation–Strain-Promoted (4 + 2) Cycloaddition
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† †Laboratory of Organic Chemistry and ‡Laboratory of Biochemistry, Wageningen University & Research, Stippeneng 4, building 124 (Helix), 6708 WE Wageningen, The Netherlands
§ AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands
*E-mail: [email protected]
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Bioconjugate Chemistry

Cite this: Bioconjugate Chem. 2017, 28, 4, 1189–1193
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https://doi.org/10.1021/acs.bioconjchem.7b00046
Published March 6, 2017

Copyright © 2017 American Chemical Society. This publication is licensed under CC-BY-NC-ND.

Abstract

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Genetically encoded tyrosine (Y-tag) can be utilized as a latent anchor for inducible and site-selective conjugation. Upon oxidation of tyrosine with mushroom tyrosinase, strain-promoted cycloaddition (SPOCQ) of the resulting 1,2-quinone with various bicyclo[6.1.0]nonyne (BCN) derivatives led to efficient conjugation. The method was applied for fluorophore labeling of laminarinase A and for the site-specific preparation of an antibody–drug conjugate.

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Introduction

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Functional modification of proteins can be achieved in a wide variety of ways. Early generation approaches, entailing the reaction with amino or thiol groups of amino acid side chains, (1-3) are effective and facile but in most cases lack selectivity due to relatively high natural abundance of lysines and cysteines in proteins. (3) Other methods involving conjugation to tyrosine, histidine, or tryptophan side chains, or to the N-terminus of proteins have also been developed. (2) As an alternative to native proteins, full control of regioselectivity can be achieved by introduction of a non-natural amino acid containing a functional handle such as an azide, a ketone or an ortho-aminophenol but often at the expense of protein expression yields. (4-6) Site-specific conjugation can also be achieved through enzymatic means, as, for example, with sortase-mediated conjugation, formyl-generating enzyme (FGE), tubulin tyrosine ligase, or activation of dihydrotetrazines by oxidation for tetrazine–TCO ligation via horseradish peroxidase or a photocatalytic agent. (7-10)
Tyrosine residues show promise as selective conjugation sites, as the relative hydrophobicity of tyrosine combined with the tendency of π–π stacking of the aromatic rings results in the limited exposure of tyrosine residues on the periphery of proteins, resulting in generally low accessibility. (11, 12) As a consequence, reactive small molecules may conjugate to tyrosines for less-selective conjugation, (13-15) while more-exposed tyrosines can allow for a wide variety of enzymatic reactions. (12, 16-20) For example, exposed tyrosine residues can be oxidized by mushroom tyrosinase to generate a 1,2-quinone, which can undergo nucleophilic attack by amines or thiols from the side chains of lysine, histidine, or cysteine. (21-23)
We recently showed that a 1,2-quinone undergoes fast strain-promoted oxidation-controlled quinone–alkyne cycloaddition (SPOCQ) with bicyclo[6.1.0]nonyne (BCN). (24-26) Here, we report that SPOCQ finds useful application in protein labeling via in situ generation of a quinone by oxidation under the action of mushroom tyrosinase (mTyr). We demonstrate that fast and complete C-terminal labeling of proteins, including an enzyme and a monoclonal antibody, can be readily achieved. The potential usefulness of the SPOCQ labeling approach is exemplified by fully controlled, site-specific generation of an antibody-drug conjugate based on anti-influenza AT1002 and the highly potent tubulin binder monomethyl auristatin F (MMAF).

Results and Discussion

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Laminarinase A

Given the inaccessibility of native tyrosine residues by mTyr, (11, 12) it was envisioned that an exposed tyrosine required installation in a protein of interest by means of a short spacer. Thus, tetra-glycyltyrosine (G4Y) was genetically fused to the C-terminus of a model protein laminarinase A (LamA), a hyperthermostable endo-β-1,3-glucanase from Pyrococcus furiosus, which contained an N-terminal His tag for purification. (16, 27) Modifications were achieved via site-directed mutagenesis and expression in Escherichia coli (see the Supporting Information section 7), resulting in a C-terminal G4Y fusion (LamA–G4Y, here referred to as Y-tag).
Purified LamA–G4Y was subjected to oxidation by catalytic mTyr (7.5 mol %) to generate the intermediate 1,2-quinone, anticipated to undergo in situ SPOCQ with BCN-modified lissamine 1, present in 4-fold excess (Figure 1). Gratifyingly, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis indicated the conversion of LamA–G4Y into the labeled product after incubation at 37 °C for 30 min with an apparent high conversion (Figure 2A). Negative controls indicated the specificity of conjugation: no fluorescently labeled LamA was detected in the absence of mTyr (lane C). Incubation with mTyr without 1 led solely to an unidentified band (lane B), most likely originating from aspecific intramolecular nucleophilic attack of an amino acid residue (e.g., Lys and His) to the generated quinone, causing it to appear at the expected position. (22, 23) No fluorescence was detected when SPOCQ was performed with wt-LamA (lane I), which implies that only the newly introduced C-terminal tyrosine is oxidized and undergoes SPOCQ. Mass spectrometry (MS) analysis of the SPOCQ reaction show a main product corresponding to the product resulting from oxidation and cycloaddition of 1 (Figure 2B,C), with a deviation of ±1 Da. Figure 2B displays MS profile of LamA–G4Y prior to oxidation, in agreement with the calculated mass, whereas Figure 2C exhibits LamA–G4Y after oxidation and SPOCQ. The desired product was identified as a peak with molecular weight 32647 Da, indicating an increase of 880 Da (calculated 879 Da) from oxidation of the tyrosine and subsequent conjugation with 1. The oxidized LamA, which underwent aspecific conjugation by a nucleophilic amino acid residue addition was also clearly detected on MS with a mass increase of approximately 13 Da. Further experiments showed that conjugation via SPOCQ could also be performed at 4 and 16 °C and ambient temperature with no observable difference in efficiency (Figure S2).

Figure 1

Figure 1. SPOCQ labeling of G4Y-tagged laminarinase A by reaction of BCN-modified reagent 1 with in situ generated 1,2-quinone. Typical reaction conditions: LamA (1.0 mg/mL), mTyr (0.3 mg/mL), and 1 (4 equiv) in 50 mM potassium phosphate buffer pH 7.3, containing 135 mM NaCl and 10% DMSO as cosolvent.

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Figure 2

Figure 2. (A) SDS-PAGE analysis of SPOCQ on LamA–G4Y and wt-LamA. (B) MS profile of LamA–G4Y. (C) MS profile of LamA–G4Y after SPOCQ with 1.

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Trastuzumab

Having successfully demonstrated the suitability of SPOCQ for C-terminal protein conjugation, its usefulness for site-specific modification of monoclonal antibodies was investigated next. Trastuzumab with genetically engineered tetra-glycyltyrosine on both light chains (Tras[LC]G4Y) was transiently expressed in CHO-K1 and purified by protein A affinity chromatography (Supporting Information section 8). Next, Tras[LC]G4Y was subjected to identical conditions for conjugation with 1 (5 equiv) by SPOCQ at 16 °C as described for LamA. As expected, SDS-PAGE analysis indicated exclusive conversion of Tras[LC]G4Y upon incubation with both 1 and mTyr (Figure S3A), while no reaction was detected on either chain for native trastuzumab under identical conditions. Mass spectrometric analysis confirmed successful addition of 1 via SPOCQ (Figure S3 B,C). It is worth pointing out that the reaction also proceeded at 4 °C, albeit much slower, but to our surprise, no fluorescent protein could be detected at higher temperature (37 °C), possibly via competing intramolecular reaction of the intermediate quinone with nearby lysine or histidine side chains (Figure S4).

AT1002

To further assess the applicability of SPOCQ for site-specific modification of monoclonal antibodies, we modified AT1002, a potent anti-influenza antibody, with a C-terminal G4Y tag (Supporting Information section 9). (28) To this end, AT1002 with a sortase tag residing on the C-terminus of each light chain was employed to obtain a C-terminally fused G4Y (AT1002[LC]G4Y). Of relevance, the obtained AT1002[LC]G4Y possesses a longer C-terminally fused tag (-G4SLPETG4Y) compared to Tras[LC]G4Y, which was anticipated to contribute favorably with regard to accessibility of the tyrosine by mTyr. (29) SPOCQ was attempted on AT1002[LC]G4Y under identical conditions compared to Tras[LC]G4Y, after which SDS-PAGE analysis demonstrated similar conjugation selectivity with high conversion: only fluorescence on the light chain was detected when reacted with mTyr and 1 (Figure 3B). Interestingly, fluorescence of the labeled AT1002 seems more intense than that of trastuzumab under identical condition, which was taken a confirmation that labeling to the light chain with a short spacer may be encumbered by less steric accessibility. Additionally, a protein band corresponding to the conjugated product was observed by SDS-PAGE analysis upon Coomassie staining, indicating a significantly higher conversion for AT1002[LC]G4Y. MS analysis confirmed SPOCQ on AT1002 (Figure 3C,D). As with trastuzumab, some nonlabeled material was still present, which may indicate that also in this case a fraction of the formed quinone reacts with lysine or histidine residues.

Figure 3

Figure 3. (A) Schematic representation of G4Y-tagged antibodies. (B) SDS-PAGE analysis of SPOCQ on AT1002[LC]G4Y and wt-AT1002. (C) MS profile of AT1002[LC]G4Y (light chain only). (D) MS spectrum of AT1002[LC]G4Y after SPOCQ with 1. (E) MS profile of AT1002[LC]G4Y after SPOCQ with 2.

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Our newly developed conjugation method was envisioned to be suitable as a site-specific approach to access antibody–drug conjugates (ADCs). These are a class of promising chemotherapeutics used for targeted treatment of tumors by combining the high cytotoxicity of a drug such as monomethyl auristatin E (MMAE) or maytansine with an antibody that has high binding affinity to the tumor cell of choice. (30) The ability of ADCs to bring highly toxic compounds selectively to the tumor cells allows the treatment of cancers while reducing the effect on healthy tissue as with traditional chemotherapies, which has led to the recent market approval of Adcetris (for the treatment of non-Hodgkin lymphoma and anaplastic large-cell lymphoma) and Kadcyla (for treatment of HER2-positive breast cancer). (31, 32) To this end, AT1002[LC]G4Y was subjected to BCN-monomethyl auristatin F conjugate (BCN-MMAF, 2) after oxidation by mTyr under identical conditions as before, with the exception that DMF was used as cosolvent instead of DMSO. Much to our satisfaction, the desired ADC was seamlessly obtained, as indicated by the expected mass increase of 1459 Da (Figure 3E), which corresponds to oxidation followed by cycloaddition (SPOCQ) with 2.

Conclusions

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We have successfully developed a site-specific bioconjugation method based on the in situ enzymatic oxidation of tyrosine by mushroom tyrosinase. Various BCN derivatives were successfully conjugated to C-terminal, oxidized tyrosine residues via SPOCQ. This cycloaddition occurs quickly, selectively, and under physiological conditions on a variety of proteins. Extensive optimization of reaction conditions is anticipated to allow fully selective and quantitative conversion. Research along those lines is currently ongoing in our laboratories. We envision that SPOCQ on tyrosine residues can be a valuable tool to create more unique, orthogonal conjugation possibilities for a wide variety of protein modifications, including the preparation of next-generation, site-specifically generated antibody–drug conjugates.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.bioconjchem.7b00046.

  • Additional method and material details, SPOCQ and expression details, gene and protein sequences, a schematic view of the reaction and corresponding mass values, and MS data. (PDF)

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Author Information

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  • Corresponding Author
    • Floris L. van Delft - †Laboratory of Organic Chemistry and ‡Laboratory of Biochemistry, Wageningen University & Research, Stippeneng 4, building 124 (Helix), 6708 WE Wageningen, The Netherlands;  AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands;  Email: [email protected]
  • Authors
    • Jorick J. Bruins - †Laboratory of Organic Chemistry and ‡Laboratory of Biochemistry, Wageningen University & Research, Stippeneng 4, building 124 (Helix), 6708 WE Wageningen, The Netherlands;  AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands;  Orcidhttp://orcid.org/0000-0003-1470-5557
    • Adrie H. Westphal - †Laboratory of Organic Chemistry and ‡Laboratory of Biochemistry, Wageningen University & Research, Stippeneng 4, building 124 (Helix), 6708 WE Wageningen, The Netherlands;  AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands
    • Bauke Albada - †Laboratory of Organic Chemistry and ‡Laboratory of Biochemistry, Wageningen University & Research, Stippeneng 4, building 124 (Helix), 6708 WE Wageningen, The Netherlands;  AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands;  Orcidhttp://orcid.org/0000-0003-3659-2434
    • Koen Wagner - AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands
    • Lina Bartels - AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands
    • Hergen Spits - AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands
    • Willem J. H. van Berkel - †Laboratory of Organic Chemistry and ‡Laboratory of Biochemistry, Wageningen University & Research, Stippeneng 4, building 124 (Helix), 6708 WE Wageningen, The Netherlands;  AIMM Therapeutics, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands;  Orcidhttp://orcid.org/0000-0002-6551-2782
  • Notes
    The authors declare the following competing financial interest(s): K.W., L.B. and H.S. declare that they are employees of AIMM therapeutics. H.S. declares that he is also an employee of the department of experimental immunology at AMC, Amsterdam. F.L.V.D. declares that he is also an employee and share-holder of Synaffix BV.

Acknowledgment

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Remon van Geel and Peter van Galen are acknowledged for providing kind assistance with the mass spectrometry measurements. This work is funded by the NWO Gravity Program Institute for Chemical Immunology (ICI).

References

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    Journal of Biological Chemistry (1998), 273 (25), 15458-15463CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    A representative set of high resoln. x-ray crystal structures of nonhomologous proteins was examd. to det. the preferred positions and orientations of noncovalent interactions between the arom. side-chains of the amino acids, Phe, Tyr, His, and Trp. To study the primary interactions between arom. amino acids, care was taken to examine only isolated pairs (dimers) of amino acids because trimers and higher order clusters of arom. amino acids behave differently than their dimer counterparts. It was found that pairs (dimers) of arom. side-chain amino acids preferentially aligned their resp. arom. rings in an off-centered parallel orientation. Further, it was found that this parallel-displaced structure was 0.5-0.75 kcal/mol more stable than a T-shaped structure for Phe interactions and 1 kcal/mol more stable than a T-shaped structure for the full set of arom. side-chain amino acids. This exptl. detd. structure and energy difference was consistent with ab initio and mol. mechanics calcns. of the benzene dimer; however, the results were not in agreement with previously published analyses of arom. amino acids in proteins. The preferred orientation was referred to as parallel displaced π-stacking.
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  12. 12
    Struck, A. W., Bennett, M. R., Shepherd, S. A., Law, B. J., Zhuo, Y., Wong, L. S., and Micklefield, J. (2016) An enzyme cascade for selective modification of tyrosine residues in structurally diverse peptides and proteins J. Am. Chem. Soc. 138, 3038– 45 DOI: 10.1021/jacs.5b10928
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    12
    An Enzyme Cascade for Selective Modification of Tyrosine Residues in Structurally Diverse Peptides and Proteins
    Struck, Anna-Winona; Bennett, Matthew R.; Shepherd, Sarah A.; Law, Brian J. C.; Zhuo, Ying; Wong, Lu Shin; Micklefield, Jason
    Journal of the American Chemical Society (2016), 138 (9), 3038-3045CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Bioorthogonal chem. enables a specific moiety in a complex biomol. to be selectively modified in the presence of many reactive functional groups and other cellular entities. Such selectivity has become indispensable in biol., enabling biomols. to be derivatized, conjugated, labeled, or immobilized for imaging, biochem. assays, or therapeutic applications. Methyltransferase enzymes (MTase) that accept analogs of the cofactor S-adenosyl methionine have been widely deployed for alkyl-diversification and bioorthogonal labeling. However, MTases typically possess tight substrate specificity. Here we introduce a more flexible methodol. for selective derivatization of phenolic moieties in complex biomols. Our approach relies on the tandem enzymic reaction of a fungal tyrosinase and the mammalian catechol-O-methyltransferase (COMT), which can effect the sequential hydroxylation of the phenolic group to give an intermediate catechol moiety that is subsequently O-alkylated. When used in this combination, the alkoxylation is highly selective for tyrosine residues in peptides and proteins, yet remarkably tolerant to changes in the peptide sequence. Tyrosinase-COMT are shown to provide highly versatile and regioselective modification of a diverse range of substrates including peptide antitumor agents, hormones, cyclic peptide antibiotics, and model proteins.
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  13. 13
    Schlick, T. L., Ding, Z., Kovacs, E. W., and Francis, M. B. (2005) Dual-surface modification of the tobacco mosaic virus J. Am. Chem. Soc. 127, 3718– 23 DOI: 10.1021/ja046239n
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    13
    Dual-surface modification of the Tobacco mosaic virus
    Schlick, Tara L.; Ding, Zhebo; Kovacs, Ernest W.; Francis, Matthew B.
    Journal of the American Chemical Society (2005), 127 (11), 3718-3723CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The protein shell of the tobacco mosaic virus (TMV) provides a robust and practical tubelike scaffold for the prepn. of nanoscale materials. To expand the range of applications for which the capsid can be used, two synthetic strategies have been developed for the attachment of new functionality to either the exterior or the interior surface of the virus. The first of these is accomplished using a highly efficient diazonium coupling/oxime formation sequence, which installs >2000 copies of a material component on the capsid exterior. Alternatively, the inner cavity of the tube can be modified by attaching amines to glutamic acid side chains through a carbodiimide coupling reaction. Both of these reactions have been demonstrated for a series of substrates, including biotin, chromophores, and crown ethers. Through the attachment of PEG polymers to the capsid exterior, org.-sol. TMV rods have been prepd. Finally, the orthogonality of these reactions has been demonstrated by installing different functional groups on the exterior and interior surfaces of the same capsid assemblies.
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  14. 14
    Ban, H., Gavrilyuk, J., and Barbas, C. F., 3rd (2010) Tyrosine bioconjugation through aqueous ene-type reactions: a click-like reaction for tyrosine J. Am. Chem. Soc. 132, 1523– 5 DOI: 10.1021/ja909062q
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    14
    Tyrosine bioconjugation through aqueous ene-type reactions: A click-like reaction for tyrosine
    Ban, Hitoshi; Gavrilyuk, Julia; Barbas, Carlos F.
    Journal of the American Chemical Society (2010), 132 (5), 1523-1525CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A new and versatile class of cyclic diazodicarboxamides that reacts efficiently and selectively with phenols and the phenolic side chain of tyrosine through an ene-like reaction is reported. This mild aq. tyrosine ligation reaction works over a broad pH range and expands the repertoire of aq. chemistries available for small mol., peptide, and protein modification. The tyrosine ligation reactions are shown to be compatible with the labeling of native enzymes and antibodies in a buffered aq. soln. This reaction provides a novel synthetic approach to bispecific antibodies. The authors believe this reaction will find broad utility in peptide and protein chem. and in the chem. of phenol-contg. compds.
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  15. 15
    Ban, H., Nagano, M., Gavrilyuk, J., Hakamata, W., Inokuma, T., and Barbas, C. F., 3rd (2013) Facile and stabile linkages through tyrosine: bioconjugation strategies with the tyrosine-click reaction Bioconjugate Chem. 24, 520– 32 DOI: 10.1021/bc300665t
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    15
    Facile and Stabile Linkages through Tyrosine: Bioconjugation Strategies with the Tyrosine-Click Reaction
    Ban, Hitoshi; Nagano, Masanobu; Gavrilyuk, Julia; Hakamata, Wataru; Inokuma, Tsubasa; Barbas, Carlos F., III
    Bioconjugate Chemistry (2013), 24 (4), 520-532CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    The scope, chemoselectivity, and utility of the click-like tyrosine labeling reaction with 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-diones (PTADs) is reported. To study the utility and chemoselectivity of PTAD derivs. in peptide and protein chem., we synthesized PTAD derivs. possessing azide, alkyne, and ketone groups and studied their reactions with amino acid derivs. and peptides of increasing complexity. With proteins we studied the compatibility of the tyrosine click reaction with cysteine and lysine-targeted labeling approaches and demonstrate that chemoselective trifunctionalization of proteins is readily achieved. In particular cases, we noted that PTAD decompn. resulted in formation of a putative isocyanate byproduct that was promiscuous in labeling. This side reaction product, however, was readily scavenged by the addn. of a small amt. of 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) to the reaction medium. To study the potential of the tyrosine click reaction to introduce poly(ethylene glycol) chains onto proteins (PEGylation), we demonstrate that this novel reagent provides for the selective PEGylation of chymotrypsinogen, whereas traditional succinimide-based PEGylation targeting lysine residues provided a more diverse range of PEGylated products. Finally, we applied the tyrosine click reaction to create a novel antibody-drug conjugate. For this purpose, we synthesized a PTAD deriv. linked to the HIV entry inhibitor aplaviroc. Labeling of the antibody trastuzumab with this reagent provided a labeled antibody conjugate that demonstrated potent HIV-1 neutralization activity demonstrating the potential of this reaction in creating protein conjugates with small mols. The tyrosine click linkage demonstrated stability to extremes of pH, temp., and exposure to human blood plasma indicating that this linkage is significantly more robust than maleimide-type linkages that are commonly employed in bioconjugations. These studies support the broad utility of this reaction in the chemoselective modification of small mols., peptides, and proteins under mild aq. conditions over a broad pH range using a wide variety of biol. acceptable buffers such as phosphate buffered saline (PBS) and 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) buffers as well as others and mixed buffered compns.
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  16. 16
    Minamihata, K., Goto, M., and Kamiya, N. (2011) Site-specific protein cross-linking by peroxidase-catalyzed activation of a tyrosine-containing peptide tag Bioconjugate Chem. 22, 74– 81 DOI: 10.1021/bc1003982
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    16
    Site-Specific Protein Cross-Linking by Peroxidase-Catalyzed Activation of a Tyrosine-Containing Peptide Tag
    Minamihata, Kosuke; Goto, Masahiro; Kamiya, Noriho
    Bioconjugate Chemistry (2011), 22 (1), 74-81CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Protein modification methods represent fundamental techniques that are applicable in many fields. In this study, a site-specific protein crosslinking based on the oxidative tyrosine coupling reaction was demonstrated. In the presence of horseradish peroxidase (HRP) and H2O2, tyrosine residues undergo one-electron oxidn. reactions and form radicals in their phenolic moieties, and these species subsequently react with each other to form dimers or further react to generate polymers. Here, a peptide-tag contg. a tyrosine residue(s) (Y-tag, of which the amino acid sequences were either GGGGY or GGYYY) was genetically introduced at the C-terminus of a model protein, Escherichia coli alk. phosphatase (BAP). Following the incubation of recombinant BAPs with HRP and H2O2, Y-tagged BAPs were efficiently cross-linked with each other, whereas wild-type BAP did not undergo crosslinking, indicating that the tyrosine residues in the Y-tags were recognized by HRP as the substrates. To det. the site-specificity of the crosslinking reaction, the Y-tag was selectively removed by thrombin digestion. The resultant BAP without the Y-tag showed no reactivity in the presence of HRP and H2O2. Conversely, Y-tagged BAPs cross-linked by HRP treatment were almost completely digested into monomeric BAP units following incubation with the protease. Moreover, cross-linked Y-tagged BAPs retained ∼95% of their native enzymic activity. These results show that HRP catalyzed the site-specific crosslinking of BAPs through tyrosine residues positioned in the C-terminal Y-tag. The site-selective enzymic oxidative tyrosine coupling reaction should offer a practical option for site-specific and covalent protein modifications.
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  17. 17
    Tilley, S. D. and Francis, M. B. (2006) Tyrosine-selective protein alkylation using pi-allylpalladium complexes J. Am. Chem. Soc. 128, 1080– 81 DOI: 10.1021/ja057106k
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    17
    Tyrosine-Selective Protein Alkylation Using π-Allylpalladium Complexes
    Tilley, S. David; Francis, Matthew B.
    Journal of the American Chemical Society (2006), 128 (4), 1080-1081CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A new protein modification reaction has been developed based on a palladium-catalyzed allylic alkylation of tyrosine residues. This technique employs electrophilic π-allyl intermediates derived from allylic acetate and carbamate precursors and can be used to modify proteins in aq. soln. at room temp. To facilitate the detection of modified proteins using SDS-PAGE anal., a fluorescent allyl acetate was synthesized and coupled to chymotrypsinogen A and bacteriophage MS2. The tyrosine selectivity of the reaction was confirmed through trypsin digest anal. The utility of the reaction was demonstrated by using taurine-derived carbamates as water solubilizing groups that are cleaved upon protein functionalization. This soly. switching technique was used to install hydrophobic farnesyl and C17 chains on chymotrypsinogen A in water using little or no cosolvent. Following this, the C17 alkylated proteins were found to assoc. with lipid vesicles. In addn. to providing a new protein modification strategy targeting an underutilized amino acid side chain, this method provides convenient access to synthetic lipoproteins.
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  18. 18
    Romanini, D. W. and Francis, M. B. (2008) Attachment of peptide building blocks to proteins through tyrosine bioconjugation Bioconjugate Chem. 19, 153– 7 DOI: 10.1021/bc700231v
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    18
    Attachment of Peptide Building Blocks to Proteins Through Tyrosine Bioconjugation
    Romanini, Dante W.; Francis, Matthew B.
    Bioconjugate Chemistry (2008), 19 (1), 153-157CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Recent efforts have yielded a no. of short peptide sequences with useful binding, sensing, and cellular uptake properties. To attach these sequences to tyrosine residues on intact proteins, a three-component Mannich-type strategy is reported. Two solid phase synthetic routes were developed to access peptides up to 20 residues in length with anilines at either the N- or C-termini. In the presence of 20 mM formaldehyde, these functional groups were coupled to tyrosine residues on proteins under mild reaction conditions. The identities of the resulting bioconjugates were confirmed using mass spectrometry and immunoblot anal. Screening expts. have demonstrated that the method is compatible with substrates contg. all of the amino acids, including lysine and cysteine residues. Importantly, tyrosine residues on proteins exhibit much faster reaction rates, allowing short peptides contg. this residue to be coupled without cross reactions.
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  19. 19
    Long, M. J. C. and Hedstrom, L. (2012) Mushroom tyrosinase oxidizes tyrosine-rich sequences to allow selective protein functionalization ChemBioChem 13, 1818– 25 DOI: 10.1002/cbic.201100792
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    19
    Mushroom Tyrosinase Oxidizes Tyrosine-Rich Sequences to Allow Selective Protein Functionalization
    Long, Marcus J. C.; Hedstrom, Lizbeth
    ChemBioChem (2012), 13 (12), 1818-1825, S1818/1-S1818/12CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
    We show that mushroom tyrosinase catalyzes the formation of reactive o-quinones on unstructured, tyrosine-rich sequences such as hemagglutinin (HA) tags (YPYDVPDYA). In the absence of exogenous nucleophiles and at low protein concns., the o-quinone decomps. with fragmentation of the HA tag. At higher protein concns. (>5 mg mL-1), crosslinking is obsd. Besthorn's reagent intercepts the o-quinone to give a characteristic pink complex that can be obsd. directly on a denaturing SDS-PAGE gel. Similar labeled species can be formed by using other nucleophiles such as Cy5-hydrazide. These reactions are selective for proteins bearing HA and other unstructured poly-tyrosine-contg. tags and can be performed in lysates to create specifically tagged proteins.
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  20. 20
    Faccio, G., Kampf, M. M., Piatti, C., Thony-Meyer, L., and Richter, M. (2014) Tyrosinase-catalyzed site-specific immobilization of engineered C-phycocyanin to surface Sci. Rep. 4, 5370 DOI: 10.1038/srep05370
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    20
    Tyrosinase-catalyzed site-specific immobilization of engineered C-phycocyanin to surface
    Faccio, Greta; Kampf, Michael M.; Piatti, Chiara; Thony-Meyer, Linda; Richter, Michael
    Scientific Reports (2014), 4 (), 5370CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
    Enzymic crosslinking of proteins is often limited by the steric availability of the target residues, as of tyrosyl side chains in the case of tyrosinase. Carrying an N-terminal peptide-tag contg. two tyrosine residues, the fluorescent protein C-phycocyanin HisCPC from Synechocystis sp. PCC6803 was crosslinked to fluorescent high-mol. wt. forms with tyrosinase. Crosslinking with tyrosinase in the presence of L-tyrosine produced non fluorescent high-mol. wt. products. Incubated in the presence of tyrosinase, HisCPC could also be immobilized to amino-modified polystyrene beads thus conferring a blue fluorescence. Crosslinking and immobilization were site-specific as both processes required the presence of the N-terminal peptide in HisCPC.
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  21. 21
    Ito, S., Kato, T., Shinpo, K., and Fujita, K. (1984) Oxidation of tyrosine residues in proteins by tyrosinase. Formation of protein-bonded 3,4-dihydroxyphenylalanine and 5-S-cysteinyl-3,4-dihydroxyphenylalanine Biochem. J. 222, 407– 11 DOI: 10.1042/bj2220407
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    21
    Oxidation of tyrosine residues in proteins by tyrosinase. Formation of protein-bonded 3,4-dihydroxyphenylalanine and 5-S-cysteinyl-3,4-dihydroxyphenylalanine
    Ito, Shosuke; Kato, Toshiaki; Shinpo, Kan; Fujita, Keisuke
    Biochemical Journal (1984), 222 (2), 407-11CODEN: BIJOAK; ISSN:0264-6021.
    A simple and rapid method was developed for the detn. of 3,4-dihydroxyphenylalanine (DOPA) and 5-S-cysteinyl-3,4-dihydroxyphenylalanine (5-S-cysteinyl-DOPA) in proteins with the use of high-pressure liq. chromatog. With this method, it was demonstrated that mushroom tyrosinase can catalyze hydroxylation of tyrosine residues in proteins to DOPA and subsequent oxidn. to dopaquinone residues. The dopaquinone residues in proteins combine with cysteine residues to form 5-S-cysteinyl-DOPA in bovine serum albumin and yeast alc. dehydrogenase, whereas DOPA is the major product in bovine insulin which lacks cysteine residues.
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  22. 22
    Tabakovic, K. and Abul-Hajj, Y. J. (1994) Reaction of lysine with estrone 3,4-o-quinone Chem. Res. Toxicol. 7, 696– 701 DOI: 10.1021/tx00041a016
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    Xu, R., Huang, X., Morgan, T. D., Prakash, O., Kramer, K. J., and Hawley, M. D. (1996) Characterization of products from the reactions of N-acetyldopamine quinone with N-acetylhistidine Arch. Biochem. Biophys. 329, 56– 64 DOI: 10.1006/abbi.1996.0191
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    Borrmann, A., Fatunsin, O., Dommerholt, J., Jonker, A. M., Lowik, D. W., van Hest, J. C., and van Delft, F. L. (2015) Strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) for fast and activatable protein conjugation Bioconjugate Chem. 26, 257– 61 DOI: 10.1021/bc500534d
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    24
    Strain-Promoted Oxidation-Controlled Cyclooctyne-1,2-Quinone Cycloaddition (SPOCQ) for Fast and Activatable Protein Conjugation
    Borrmann, Annika; Fatunsin, Olumide; Dommerholt, Jan; Jonker, Anika M.; Loewik, Dennis W. P. M.; van Hest, Jan C. M.; van Delft, Floris L.
    Bioconjugate Chemistry (2015), 26 (2), 257-261CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    A main challenge in the area of bioconjugation is to devise reactions that are both activatable and fast. Here, we introduce a temporally controlled reaction between cyclooctynes and 1,2-quinones, induced by facile oxidn. of 1,2-catechols. This so-called strain-promoted oxidn.-controlled cyclooctyne-1,2-quinone cycloaddn. (SPOCQ) shows a remarkably high reaction rate when performed with bicyclononyne (BCN), out-competing the well-known cycloaddn. of azides and BCN by 3 orders of magnitude, thereby allowing a new level of orthogonality in protein conjugation.
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  25. 25
    Jonker, A. M., Borrmann, A., van Eck, E. R., van Delft, F. L., Lowik, D. W., and van Hest, J. C. (2015) A fast and activatable cross-linking strategy for hydrogel formation Adv. Mater. 27, 1235– 40 DOI: 10.1002/adma.201404448
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    25
    A Fast and Activatable Cross-Linking Strategy for Hydrogel Formation
    Jonker, Anika M.; Borrmann, Annika; van Eck, Ernst R. H.; van Delft, Floris L.; Loewik, Dennis W. P. M.; van Hest, Jan C. M.
    Advanced Materials (Weinheim, Germany) (2015), 27 (7), 1235-1240CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The study reports a fast and activatible crosslinking method for hydrogel formation using a a strain-promoted oxidn. controlled cyclooctyne-1,2-quinone cycloaddn.
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  26. 26
    Dommerholt, J., Schmidt, S., Temming, R., Hendriks, L. J., Rutjes, F. P., van Hest, J. C., Lefeber, D. J., Friedl, P., and van Delft, F. L. (2010) Readily accessible bicyclononynes for bioorthogonal labeling and three-dimensional imaging of living cells Angew. Chem., Int. Ed. 49, 9422– 5 DOI: 10.1002/anie.201003761
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    26
    Readily accessible bicyclononynes for bioorthogonal labeling and three-dimensional imaging of living cells
    Dommerholt, Jan; Schmidt, Samuel; Temming, Rinske; Hendriks, Linda J. A.; Rutjes, Floris P. J. T.; van Hest, Jan C. M.; Lefeber, Dirk J.; Friedl, Peter; van Delft, Floris L.
    Angewandte Chemie, International Edition (2010), 49 (49), 9422-9425, S9422/1-S9422/22CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    We reported to use bicyclo[6.1.0]nonyne (BCN) as a novel ring-strained alkyne for metal-free cycloaddn. reactions with azides and nitrones. The complexes were synthesized and used for bioorthogonal labeling/three-dimensional imaging of living cells.
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    Przybysz, A., Volmer, A. A., Westphal, A. H., and van Berkel, W. J. (2014) Bifunctional immobilization of a hyperthermostable endo-beta-1,3-glucanase Appl. Microbiol. Biotechnol. 98, 1155– 63 DOI: 10.1007/s00253-013-4953-3
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    There is no corresponding record for this reference.
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    Wagner, K., Kwakkenbos, M. J., Claassen, Y. B., Maijoor, K., Bohne, M., van der Sluijs, K. F., Witte, M. D., van Zoelen, D. J., Cornelissen, L. A., and Beaumont, T. 2014, Bispecific antibody generated with sortase and click chemistry has broad antiinfluenza virus activity Proc. Natl. Acad. Sci. U. S. A. 111, 16820– 5 DOI: 10.1073/pnas.1408605111
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    28
    Bispecific antibody generated with sortase and click chemistry has broad antiinfluenza virus activity
    Wagner, Koen; Kwakkenbos, Mark J.; Claassen, Yvonne B.; Maijoor, Kelly; Boehne, Martino; van der Sluijs, Koenraad F.; Witte, Martin D.; van Zoelen, Diana J.; Cornelissen, Lisette A.; Beaumont, Tim; Bakker, Arjen Q.; Ploegh, Hidde L.; Spits, Hergen
    Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (47), 16820-16825CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Bispecific antibodies have therapeutic potential by expanding the functions of conventional antibodies. Many different formats of bispecific antibodies have meanwhile been developed. Most are genetic modifications of the antibody backbone to facilitate incorporation of two different variable domains into a single mol. Here, we present a bispecific format where we have fused two full-sized IgG antibodies via their C termini using sortase trans-peptidation and click chem. to create a covalently linked IgG antibody heterodimer. By linking two potent anti-influenza A antibodies together, we have generated a full antibody dimer with bispecific activity that retains the activity and stability of the two fusion partners.
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  29. 29
    Dorywalska, M., Strop, P., Melton-Witt, J. A., Hasa-Moreno, A., Farias, S. E., Galindo Casas, M., Delaria, K., Lui, V., Poulsen, K., and Loo, C. 2015, Effect of Attachment Site on Stability of Cleavable Antibody Drug Conjugates Bioconjugate Chem. 26, 650– 659 DOI: 10.1021/bc5005747
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    29
    Effect of Attachment Site on Stability of Cleavable Antibody Drug Conjugates
    Dorywalska, Magdalena; Strop, Pavel; Melton-Witt, Jody A.; Hasa-Moreno, Adela; Farias, Santiago E.; Galindo Casas, Meritxell; Delaria, Kathy; Lui, Victor; Poulsen, Kris; Loo, Carole; Krimm, Stellanie; Bolton, Gary; Moine, Ludivine; Dushin, Russell; Tran, Thomas-Toan; Liu, Shu-Hui; Rickert, Mathias; Foletti, Davide; Shelton, David L.; Pons, Jaume; Rajpal, Arvind
    Bioconjugate Chemistry (2015), 26 (4), 650-659CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    The systemic stability of the antibody-drug linker is crucial for delivery of an intact antibody-drug conjugate (ADC) to target-expressing tumors. Linkers stable in circulation but readily processed in the target cell are necessary for both safety and potency of the delivered conjugate. Here, we report a range of stabilities for an auristatin-based payload site-specifically attached through a cleavable valine-citrulline-p-aminobenzylcarbamate (VC-PABC) linker across various sites on an antibody. We demonstrate that the conjugation site plays an important role in detg. VC-PABC linker stability in mouse plasma, and that the stability of the linker pos. correlates with ADC cytotoxic potency both in vitro and in vivo. Furthermore, we show that the VC-PABC cleavage in mouse plasma is not mediated by Cathepsin B, the protease thought to be primarily responsible for linker processing in the lysosomal degrdn. pathway. Although the VC-PABC cleavage is not detected in primate plasma in vitro, linker stabilization in the mouse is an essential prerequisite for designing successful efficacy and safety studies in rodents during preclin. stages of ADC programs. The divergence of linker metab. in mouse plasma and its intracellular cleavage offers an opportunity for linker optimization in the circulation without compromising its efficient payload release in the target cell.
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    Chari, R. V., Miller, M. L., and Widdison, W. C. (2014) Antibody-drug conjugates: an emerging concept in cancer therapy Angew. Chem., Int. Ed. 53, 3796– 827 DOI: 10.1002/anie.201307628
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    Antibody-Drug Conjugates: An Emerging Concept in Cancer Therapy
    Chari, Ravi V. J.; Miller, Michael L.; Widdison, Wayne C.
    Angewandte Chemie, International Edition (2014), 53 (15), 3796-3827CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody-drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compd. selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado-trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first-generation ADCs have led to improvements in every aspect of this technol., i.e., the antibody, the cytotoxic compd., and the linker connecting them, leading to the current successes. The design of ADCs currently in clin. development, and results from mechanistic studies and preclin. and clin. evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.
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    Younes, A., Bartlett, N. L., Leonard, J. P., Kennedy, D. A., Lynch, C. M., Sievers, E. L., and Forero-Torres, A. (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas N. Engl. J. Med. 363, 1812– 21 DOI: 10.1056/NEJMoa1002965
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    Brentuximab vedotin (SGN-35) for relapsed Cd30-positive lymphomas
    Younes, Anas; Bartlett, Nancy L.; Leonard, John P.; Kennedy, Dana A.; Lynch, Carmel M.; Sievers, Eric L.; Forero-Torres, Andres
    New England Journal of Medicine (2010), 363 (19), 1812-1821CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
    BACKGROUND: Hodgkin's lymphoma and anaplastic large-cell lymphoma are the two most common tumors expressing CD30. Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity. To enhance the antitumor activity of CD30-directed therapy, the antitubulin agent monomethyl auristatin E (MMAE) was attached to a CD30-specific monoclonal antibody by an enzyme-cleavable linker, producing the antibody-drug conjugate brentuximab vedotin (SGN-35). METHODS: In this phase 1, open-label, multicenter dose-escalation study, we administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg per kg of body wt.) every 3 wk to 45 patients with relapsed or refractory CD30-pos. hematol. Cancers, primarily Hodgkin's lymphoma and anaplastic large-cell lymphoma. Patients had received a median of three previous chemotherapy regimens (range, one to seven), and 73% had undergone autologous stem-cell transplantation. RESULTS: The max. tolerated dose was 1.8 mg per kg, administered every 3 wk. Objective responses, including 11 complete remissions, were obsd. in 17 patients. Of 12 patients who received the 1.8-mg-per-kilogram dose, 6 (50%) had an objective response. The median duration of response was at least 9.7 mo. Tumor regression was obsd. in 36 of 42 patients who could be evaluated (86%). The most common adverse events were fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. CONCLUSIONS: Brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-pos. lymphomas in this phase 1 study. Treatment was assocd. primarily with grade 1 or 2 (mild-to-moderate) toxic effects.
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    Verma, S., Miles, D., Gianni, L., Krop, I. E., Welslau, M., Baselga, J., Pegram, M., Oh, D. Y., Dieras, V., and Guardino, E. 2012, Trastuzumab emtansine for HER2-positive advanced breast cancer N. Engl. J. Med. 367, 1783– 91 DOI: 10.1056/NEJMoa1209124
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    Trastuzumab emtansine for HER2-positive advanced breast cancer
    Verma, Sunil; Miles, David; Gianni, Luca; Krop, Ian E.; Welslau, Manfred; Baselga, Jose; Pegram, Mark; Oh, Do-Youn; Dieras, Veronique; Guardino, Ellie; Fang, Liang; Lu, Michael W.; Olsen, Steven; Blackwell, Kim
    New England Journal of Medicine (2012), 367 (19), 1783-1791CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
    BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. METHODS: We randomly assigned patients with HER2-pos. advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. RESULTS: Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 mo with T-DM1 vs. 6.4 mo with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim anal. crossed the stopping boundary for efficacy (30.9 mo vs. 25.1 mo; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all addnl. secondary end points favored T-DM1. Rates of grade 3 or above were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. CONCLUSIONS: T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-pos. advanced breast cancer previously treated with trastuzumab and a taxane.
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Cite this: Bioconjugate Chem. 2017, 28, 4, 1189–1193
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https://doi.org/10.1021/acs.bioconjchem.7b00046
Published March 6, 2017

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  • Abstract

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    Figure 1

    Figure 1. SPOCQ labeling of G4Y-tagged laminarinase A by reaction of BCN-modified reagent 1 with in situ generated 1,2-quinone. Typical reaction conditions: LamA (1.0 mg/mL), mTyr (0.3 mg/mL), and 1 (4 equiv) in 50 mM potassium phosphate buffer pH 7.3, containing 135 mM NaCl and 10% DMSO as cosolvent.

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    Figure 2

    Figure 2. (A) SDS-PAGE analysis of SPOCQ on LamA–G4Y and wt-LamA. (B) MS profile of LamA–G4Y. (C) MS profile of LamA–G4Y after SPOCQ with 1.

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    Figure 3

    Figure 3. (A) Schematic representation of G4Y-tagged antibodies. (B) SDS-PAGE analysis of SPOCQ on AT1002[LC]G4Y and wt-AT1002. (C) MS profile of AT1002[LC]G4Y (light chain only). (D) MS spectrum of AT1002[LC]G4Y after SPOCQ with 1. (E) MS profile of AT1002[LC]G4Y after SPOCQ with 2.

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      To further our aim of synthesizing aldehyde-tagged proteins for research and biotechnol. applications, we developed methods for recombinant prodn. of aerobic formylglycine-generating enzyme (FGE) in good yield. We then optimized the FGE biocatalytic reaction conditions for conversion of cysteine to formylglycine in aldehyde tags on intact monoclonal antibodies. During the development of these conditions, we discovered that pretreating FGE with copper(II) is required for high turnover rates and yields. After further investigation, we confirmed that both aerobic prokaryotic (Streptomyces coelicolor) and eukaryotic (Homo sapiens) FGEs contain a copper cofactor. The complete kinetic parameters for both forms of FGE are described, along with a proposed mechanism for FGE catalysis that accounts for the copper-dependent activity.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKhsLvN&md5=580235fe160698373c76b21ce354d61b
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      Zhang, Han; Trout, William S.; Liu, Shuang; Andrade, Gabriel A.; Hudson, Devin A.; Scinto, Samuel L.; Dicker, Kevin T.; Li, Yi; Lazouski, Nikifar; Rosenthal, Joel; Thorpe, Colin; Jia, Xinqiao; Fox, Joseph M.
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      Rapid bioorthogonal reactivity can be induced by controllable, catalytic stimuli using air as the oxidant. Methylene blue (4 μM) irradiated with red light (660 nm) catalyzes the rapid oxidn. of a dihydrotetrazine to a tetrazine thereby turning on reactivity toward trans-cyclooctene dienophiles. Alternately, the aerial oxidn. of dihydrotetrazines can be efficiently catalyzed by nanomolar levels of horseradish peroxidase under peroxide-free conditions. Selection of dihydrotetrazine/tetrazine pairs of sufficient kinetic stability in aerobic aq. solns. is key to the success of these approaches. In this work, polymer fibers carrying latent dihydrotetrazines were catalytically activated and covalently modified by trans-cyclooctene conjugates of small mols., peptides, and proteins. In addn. to visualization with fluorophores, fibers conjugated to a cell adhesive peptide exhibited a dramatically increased ability to mediate contact guidance of cells.
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      A representative set of high resoln. x-ray crystal structures of nonhomologous proteins was examd. to det. the preferred positions and orientations of noncovalent interactions between the arom. side-chains of the amino acids, Phe, Tyr, His, and Trp. To study the primary interactions between arom. amino acids, care was taken to examine only isolated pairs (dimers) of amino acids because trimers and higher order clusters of arom. amino acids behave differently than their dimer counterparts. It was found that pairs (dimers) of arom. side-chain amino acids preferentially aligned their resp. arom. rings in an off-centered parallel orientation. Further, it was found that this parallel-displaced structure was 0.5-0.75 kcal/mol more stable than a T-shaped structure for Phe interactions and 1 kcal/mol more stable than a T-shaped structure for the full set of arom. side-chain amino acids. This exptl. detd. structure and energy difference was consistent with ab initio and mol. mechanics calcns. of the benzene dimer; however, the results were not in agreement with previously published analyses of arom. amino acids in proteins. The preferred orientation was referred to as parallel displaced π-stacking.
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      Struck, A. W., Bennett, M. R., Shepherd, S. A., Law, B. J., Zhuo, Y., Wong, L. S., and Micklefield, J. (2016) An enzyme cascade for selective modification of tyrosine residues in structurally diverse peptides and proteins J. Am. Chem. Soc. 138, 3038– 45 DOI: 10.1021/jacs.5b10928
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      An Enzyme Cascade for Selective Modification of Tyrosine Residues in Structurally Diverse Peptides and Proteins
      Struck, Anna-Winona; Bennett, Matthew R.; Shepherd, Sarah A.; Law, Brian J. C.; Zhuo, Ying; Wong, Lu Shin; Micklefield, Jason
      Journal of the American Chemical Society (2016), 138 (9), 3038-3045CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Bioorthogonal chem. enables a specific moiety in a complex biomol. to be selectively modified in the presence of many reactive functional groups and other cellular entities. Such selectivity has become indispensable in biol., enabling biomols. to be derivatized, conjugated, labeled, or immobilized for imaging, biochem. assays, or therapeutic applications. Methyltransferase enzymes (MTase) that accept analogs of the cofactor S-adenosyl methionine have been widely deployed for alkyl-diversification and bioorthogonal labeling. However, MTases typically possess tight substrate specificity. Here we introduce a more flexible methodol. for selective derivatization of phenolic moieties in complex biomols. Our approach relies on the tandem enzymic reaction of a fungal tyrosinase and the mammalian catechol-O-methyltransferase (COMT), which can effect the sequential hydroxylation of the phenolic group to give an intermediate catechol moiety that is subsequently O-alkylated. When used in this combination, the alkoxylation is highly selective for tyrosine residues in peptides and proteins, yet remarkably tolerant to changes in the peptide sequence. Tyrosinase-COMT are shown to provide highly versatile and regioselective modification of a diverse range of substrates including peptide antitumor agents, hormones, cyclic peptide antibiotics, and model proteins.
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      Schlick, Tara L.; Ding, Zhebo; Kovacs, Ernest W.; Francis, Matthew B.
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      The protein shell of the tobacco mosaic virus (TMV) provides a robust and practical tubelike scaffold for the prepn. of nanoscale materials. To expand the range of applications for which the capsid can be used, two synthetic strategies have been developed for the attachment of new functionality to either the exterior or the interior surface of the virus. The first of these is accomplished using a highly efficient diazonium coupling/oxime formation sequence, which installs >2000 copies of a material component on the capsid exterior. Alternatively, the inner cavity of the tube can be modified by attaching amines to glutamic acid side chains through a carbodiimide coupling reaction. Both of these reactions have been demonstrated for a series of substrates, including biotin, chromophores, and crown ethers. Through the attachment of PEG polymers to the capsid exterior, org.-sol. TMV rods have been prepd. Finally, the orthogonality of these reactions has been demonstrated by installing different functional groups on the exterior and interior surfaces of the same capsid assemblies.
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      Journal of the American Chemical Society (2010), 132 (5), 1523-1525CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A new and versatile class of cyclic diazodicarboxamides that reacts efficiently and selectively with phenols and the phenolic side chain of tyrosine through an ene-like reaction is reported. This mild aq. tyrosine ligation reaction works over a broad pH range and expands the repertoire of aq. chemistries available for small mol., peptide, and protein modification. The tyrosine ligation reactions are shown to be compatible with the labeling of native enzymes and antibodies in a buffered aq. soln. This reaction provides a novel synthetic approach to bispecific antibodies. The authors believe this reaction will find broad utility in peptide and protein chem. and in the chem. of phenol-contg. compds.
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    15. 15
      Ban, H., Nagano, M., Gavrilyuk, J., Hakamata, W., Inokuma, T., and Barbas, C. F., 3rd (2013) Facile and stabile linkages through tyrosine: bioconjugation strategies with the tyrosine-click reaction Bioconjugate Chem. 24, 520– 32 DOI: 10.1021/bc300665t
      15
      Facile and Stabile Linkages through Tyrosine: Bioconjugation Strategies with the Tyrosine-Click Reaction
      Ban, Hitoshi; Nagano, Masanobu; Gavrilyuk, Julia; Hakamata, Wataru; Inokuma, Tsubasa; Barbas, Carlos F., III
      Bioconjugate Chemistry (2013), 24 (4), 520-532CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      The scope, chemoselectivity, and utility of the click-like tyrosine labeling reaction with 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-diones (PTADs) is reported. To study the utility and chemoselectivity of PTAD derivs. in peptide and protein chem., we synthesized PTAD derivs. possessing azide, alkyne, and ketone groups and studied their reactions with amino acid derivs. and peptides of increasing complexity. With proteins we studied the compatibility of the tyrosine click reaction with cysteine and lysine-targeted labeling approaches and demonstrate that chemoselective trifunctionalization of proteins is readily achieved. In particular cases, we noted that PTAD decompn. resulted in formation of a putative isocyanate byproduct that was promiscuous in labeling. This side reaction product, however, was readily scavenged by the addn. of a small amt. of 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) to the reaction medium. To study the potential of the tyrosine click reaction to introduce poly(ethylene glycol) chains onto proteins (PEGylation), we demonstrate that this novel reagent provides for the selective PEGylation of chymotrypsinogen, whereas traditional succinimide-based PEGylation targeting lysine residues provided a more diverse range of PEGylated products. Finally, we applied the tyrosine click reaction to create a novel antibody-drug conjugate. For this purpose, we synthesized a PTAD deriv. linked to the HIV entry inhibitor aplaviroc. Labeling of the antibody trastuzumab with this reagent provided a labeled antibody conjugate that demonstrated potent HIV-1 neutralization activity demonstrating the potential of this reaction in creating protein conjugates with small mols. The tyrosine click linkage demonstrated stability to extremes of pH, temp., and exposure to human blood plasma indicating that this linkage is significantly more robust than maleimide-type linkages that are commonly employed in bioconjugations. These studies support the broad utility of this reaction in the chemoselective modification of small mols., peptides, and proteins under mild aq. conditions over a broad pH range using a wide variety of biol. acceptable buffers such as phosphate buffered saline (PBS) and 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) buffers as well as others and mixed buffered compns.
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    16. 16
      Minamihata, K., Goto, M., and Kamiya, N. (2011) Site-specific protein cross-linking by peroxidase-catalyzed activation of a tyrosine-containing peptide tag Bioconjugate Chem. 22, 74– 81 DOI: 10.1021/bc1003982
      16
      Site-Specific Protein Cross-Linking by Peroxidase-Catalyzed Activation of a Tyrosine-Containing Peptide Tag
      Minamihata, Kosuke; Goto, Masahiro; Kamiya, Noriho
      Bioconjugate Chemistry (2011), 22 (1), 74-81CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Protein modification methods represent fundamental techniques that are applicable in many fields. In this study, a site-specific protein crosslinking based on the oxidative tyrosine coupling reaction was demonstrated. In the presence of horseradish peroxidase (HRP) and H2O2, tyrosine residues undergo one-electron oxidn. reactions and form radicals in their phenolic moieties, and these species subsequently react with each other to form dimers or further react to generate polymers. Here, a peptide-tag contg. a tyrosine residue(s) (Y-tag, of which the amino acid sequences were either GGGGY or GGYYY) was genetically introduced at the C-terminus of a model protein, Escherichia coli alk. phosphatase (BAP). Following the incubation of recombinant BAPs with HRP and H2O2, Y-tagged BAPs were efficiently cross-linked with each other, whereas wild-type BAP did not undergo crosslinking, indicating that the tyrosine residues in the Y-tags were recognized by HRP as the substrates. To det. the site-specificity of the crosslinking reaction, the Y-tag was selectively removed by thrombin digestion. The resultant BAP without the Y-tag showed no reactivity in the presence of HRP and H2O2. Conversely, Y-tagged BAPs cross-linked by HRP treatment were almost completely digested into monomeric BAP units following incubation with the protease. Moreover, cross-linked Y-tagged BAPs retained ∼95% of their native enzymic activity. These results show that HRP catalyzed the site-specific crosslinking of BAPs through tyrosine residues positioned in the C-terminal Y-tag. The site-selective enzymic oxidative tyrosine coupling reaction should offer a practical option for site-specific and covalent protein modifications.
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    17. 17
      Tilley, S. D. and Francis, M. B. (2006) Tyrosine-selective protein alkylation using pi-allylpalladium complexes J. Am. Chem. Soc. 128, 1080– 81 DOI: 10.1021/ja057106k
      17
      Tyrosine-Selective Protein Alkylation Using π-Allylpalladium Complexes
      Tilley, S. David; Francis, Matthew B.
      Journal of the American Chemical Society (2006), 128 (4), 1080-1081CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A new protein modification reaction has been developed based on a palladium-catalyzed allylic alkylation of tyrosine residues. This technique employs electrophilic π-allyl intermediates derived from allylic acetate and carbamate precursors and can be used to modify proteins in aq. soln. at room temp. To facilitate the detection of modified proteins using SDS-PAGE anal., a fluorescent allyl acetate was synthesized and coupled to chymotrypsinogen A and bacteriophage MS2. The tyrosine selectivity of the reaction was confirmed through trypsin digest anal. The utility of the reaction was demonstrated by using taurine-derived carbamates as water solubilizing groups that are cleaved upon protein functionalization. This soly. switching technique was used to install hydrophobic farnesyl and C17 chains on chymotrypsinogen A in water using little or no cosolvent. Following this, the C17 alkylated proteins were found to assoc. with lipid vesicles. In addn. to providing a new protein modification strategy targeting an underutilized amino acid side chain, this method provides convenient access to synthetic lipoproteins.
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    18. 18
      Romanini, D. W. and Francis, M. B. (2008) Attachment of peptide building blocks to proteins through tyrosine bioconjugation Bioconjugate Chem. 19, 153– 7 DOI: 10.1021/bc700231v
      18
      Attachment of Peptide Building Blocks to Proteins Through Tyrosine Bioconjugation
      Romanini, Dante W.; Francis, Matthew B.
      Bioconjugate Chemistry (2008), 19 (1), 153-157CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Recent efforts have yielded a no. of short peptide sequences with useful binding, sensing, and cellular uptake properties. To attach these sequences to tyrosine residues on intact proteins, a three-component Mannich-type strategy is reported. Two solid phase synthetic routes were developed to access peptides up to 20 residues in length with anilines at either the N- or C-termini. In the presence of 20 mM formaldehyde, these functional groups were coupled to tyrosine residues on proteins under mild reaction conditions. The identities of the resulting bioconjugates were confirmed using mass spectrometry and immunoblot anal. Screening expts. have demonstrated that the method is compatible with substrates contg. all of the amino acids, including lysine and cysteine residues. Importantly, tyrosine residues on proteins exhibit much faster reaction rates, allowing short peptides contg. this residue to be coupled without cross reactions.
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    19. 19
      Long, M. J. C. and Hedstrom, L. (2012) Mushroom tyrosinase oxidizes tyrosine-rich sequences to allow selective protein functionalization ChemBioChem 13, 1818– 25 DOI: 10.1002/cbic.201100792
      19
      Mushroom Tyrosinase Oxidizes Tyrosine-Rich Sequences to Allow Selective Protein Functionalization
      Long, Marcus J. C.; Hedstrom, Lizbeth
      ChemBioChem (2012), 13 (12), 1818-1825, S1818/1-S1818/12CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We show that mushroom tyrosinase catalyzes the formation of reactive o-quinones on unstructured, tyrosine-rich sequences such as hemagglutinin (HA) tags (YPYDVPDYA). In the absence of exogenous nucleophiles and at low protein concns., the o-quinone decomps. with fragmentation of the HA tag. At higher protein concns. (>5 mg mL-1), crosslinking is obsd. Besthorn's reagent intercepts the o-quinone to give a characteristic pink complex that can be obsd. directly on a denaturing SDS-PAGE gel. Similar labeled species can be formed by using other nucleophiles such as Cy5-hydrazide. These reactions are selective for proteins bearing HA and other unstructured poly-tyrosine-contg. tags and can be performed in lysates to create specifically tagged proteins.
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    20. 20
      Faccio, G., Kampf, M. M., Piatti, C., Thony-Meyer, L., and Richter, M. (2014) Tyrosinase-catalyzed site-specific immobilization of engineered C-phycocyanin to surface Sci. Rep. 4, 5370 DOI: 10.1038/srep05370
      20
      Tyrosinase-catalyzed site-specific immobilization of engineered C-phycocyanin to surface
      Faccio, Greta; Kampf, Michael M.; Piatti, Chiara; Thony-Meyer, Linda; Richter, Michael
      Scientific Reports (2014), 4 (), 5370CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      Enzymic crosslinking of proteins is often limited by the steric availability of the target residues, as of tyrosyl side chains in the case of tyrosinase. Carrying an N-terminal peptide-tag contg. two tyrosine residues, the fluorescent protein C-phycocyanin HisCPC from Synechocystis sp. PCC6803 was crosslinked to fluorescent high-mol. wt. forms with tyrosinase. Crosslinking with tyrosinase in the presence of L-tyrosine produced non fluorescent high-mol. wt. products. Incubated in the presence of tyrosinase, HisCPC could also be immobilized to amino-modified polystyrene beads thus conferring a blue fluorescence. Crosslinking and immobilization were site-specific as both processes required the presence of the N-terminal peptide in HisCPC.
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    21. 21
      Ito, S., Kato, T., Shinpo, K., and Fujita, K. (1984) Oxidation of tyrosine residues in proteins by tyrosinase. Formation of protein-bonded 3,4-dihydroxyphenylalanine and 5-S-cysteinyl-3,4-dihydroxyphenylalanine Biochem. J. 222, 407– 11 DOI: 10.1042/bj2220407
      21
      Oxidation of tyrosine residues in proteins by tyrosinase. Formation of protein-bonded 3,4-dihydroxyphenylalanine and 5-S-cysteinyl-3,4-dihydroxyphenylalanine
      Ito, Shosuke; Kato, Toshiaki; Shinpo, Kan; Fujita, Keisuke
      Biochemical Journal (1984), 222 (2), 407-11CODEN: BIJOAK; ISSN:0264-6021.
      A simple and rapid method was developed for the detn. of 3,4-dihydroxyphenylalanine (DOPA) and 5-S-cysteinyl-3,4-dihydroxyphenylalanine (5-S-cysteinyl-DOPA) in proteins with the use of high-pressure liq. chromatog. With this method, it was demonstrated that mushroom tyrosinase can catalyze hydroxylation of tyrosine residues in proteins to DOPA and subsequent oxidn. to dopaquinone residues. The dopaquinone residues in proteins combine with cysteine residues to form 5-S-cysteinyl-DOPA in bovine serum albumin and yeast alc. dehydrogenase, whereas DOPA is the major product in bovine insulin which lacks cysteine residues.
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    22. 22
      Tabakovic, K. and Abul-Hajj, Y. J. (1994) Reaction of lysine with estrone 3,4-o-quinone Chem. Res. Toxicol. 7, 696– 701 DOI: 10.1021/tx00041a016
      There is no corresponding record for this reference.
    23. 23
      Xu, R., Huang, X., Morgan, T. D., Prakash, O., Kramer, K. J., and Hawley, M. D. (1996) Characterization of products from the reactions of N-acetyldopamine quinone with N-acetylhistidine Arch. Biochem. Biophys. 329, 56– 64 DOI: 10.1006/abbi.1996.0191
      There is no corresponding record for this reference.
    24. 24
      Borrmann, A., Fatunsin, O., Dommerholt, J., Jonker, A. M., Lowik, D. W., van Hest, J. C., and van Delft, F. L. (2015) Strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) for fast and activatable protein conjugation Bioconjugate Chem. 26, 257– 61 DOI: 10.1021/bc500534d
      24
      Strain-Promoted Oxidation-Controlled Cyclooctyne-1,2-Quinone Cycloaddition (SPOCQ) for Fast and Activatable Protein Conjugation
      Borrmann, Annika; Fatunsin, Olumide; Dommerholt, Jan; Jonker, Anika M.; Loewik, Dennis W. P. M.; van Hest, Jan C. M.; van Delft, Floris L.
      Bioconjugate Chemistry (2015), 26 (2), 257-261CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      A main challenge in the area of bioconjugation is to devise reactions that are both activatable and fast. Here, we introduce a temporally controlled reaction between cyclooctynes and 1,2-quinones, induced by facile oxidn. of 1,2-catechols. This so-called strain-promoted oxidn.-controlled cyclooctyne-1,2-quinone cycloaddn. (SPOCQ) shows a remarkably high reaction rate when performed with bicyclononyne (BCN), out-competing the well-known cycloaddn. of azides and BCN by 3 orders of magnitude, thereby allowing a new level of orthogonality in protein conjugation.
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    25. 25
      Jonker, A. M., Borrmann, A., van Eck, E. R., van Delft, F. L., Lowik, D. W., and van Hest, J. C. (2015) A fast and activatable cross-linking strategy for hydrogel formation Adv. Mater. 27, 1235– 40 DOI: 10.1002/adma.201404448
      25
      A Fast and Activatable Cross-Linking Strategy for Hydrogel Formation
      Jonker, Anika M.; Borrmann, Annika; van Eck, Ernst R. H.; van Delft, Floris L.; Loewik, Dennis W. P. M.; van Hest, Jan C. M.
      Advanced Materials (Weinheim, Germany) (2015), 27 (7), 1235-1240CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The study reports a fast and activatible crosslinking method for hydrogel formation using a a strain-promoted oxidn. controlled cyclooctyne-1,2-quinone cycloaddn.
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    26. 26
      Dommerholt, J., Schmidt, S., Temming, R., Hendriks, L. J., Rutjes, F. P., van Hest, J. C., Lefeber, D. J., Friedl, P., and van Delft, F. L. (2010) Readily accessible bicyclononynes for bioorthogonal labeling and three-dimensional imaging of living cells Angew. Chem., Int. Ed. 49, 9422– 5 DOI: 10.1002/anie.201003761
      26
      Readily accessible bicyclononynes for bioorthogonal labeling and three-dimensional imaging of living cells
      Dommerholt, Jan; Schmidt, Samuel; Temming, Rinske; Hendriks, Linda J. A.; Rutjes, Floris P. J. T.; van Hest, Jan C. M.; Lefeber, Dirk J.; Friedl, Peter; van Delft, Floris L.
      Angewandte Chemie, International Edition (2010), 49 (49), 9422-9425, S9422/1-S9422/22CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We reported to use bicyclo[6.1.0]nonyne (BCN) as a novel ring-strained alkyne for metal-free cycloaddn. reactions with azides and nitrones. The complexes were synthesized and used for bioorthogonal labeling/three-dimensional imaging of living cells.
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    27. 27
      Przybysz, A., Volmer, A. A., Westphal, A. H., and van Berkel, W. J. (2014) Bifunctional immobilization of a hyperthermostable endo-beta-1,3-glucanase Appl. Microbiol. Biotechnol. 98, 1155– 63 DOI: 10.1007/s00253-013-4953-3
      There is no corresponding record for this reference.
    28. 28
      Wagner, K., Kwakkenbos, M. J., Claassen, Y. B., Maijoor, K., Bohne, M., van der Sluijs, K. F., Witte, M. D., van Zoelen, D. J., Cornelissen, L. A., and Beaumont, T. 2014, Bispecific antibody generated with sortase and click chemistry has broad antiinfluenza virus activity Proc. Natl. Acad. Sci. U. S. A. 111, 16820– 5 DOI: 10.1073/pnas.1408605111
      28
      Bispecific antibody generated with sortase and click chemistry has broad antiinfluenza virus activity
      Wagner, Koen; Kwakkenbos, Mark J.; Claassen, Yvonne B.; Maijoor, Kelly; Boehne, Martino; van der Sluijs, Koenraad F.; Witte, Martin D.; van Zoelen, Diana J.; Cornelissen, Lisette A.; Beaumont, Tim; Bakker, Arjen Q.; Ploegh, Hidde L.; Spits, Hergen
      Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (47), 16820-16825CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Bispecific antibodies have therapeutic potential by expanding the functions of conventional antibodies. Many different formats of bispecific antibodies have meanwhile been developed. Most are genetic modifications of the antibody backbone to facilitate incorporation of two different variable domains into a single mol. Here, we present a bispecific format where we have fused two full-sized IgG antibodies via their C termini using sortase trans-peptidation and click chem. to create a covalently linked IgG antibody heterodimer. By linking two potent anti-influenza A antibodies together, we have generated a full antibody dimer with bispecific activity that retains the activity and stability of the two fusion partners.
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    29. 29
      Dorywalska, M., Strop, P., Melton-Witt, J. A., Hasa-Moreno, A., Farias, S. E., Galindo Casas, M., Delaria, K., Lui, V., Poulsen, K., and Loo, C. 2015, Effect of Attachment Site on Stability of Cleavable Antibody Drug Conjugates Bioconjugate Chem. 26, 650– 659 DOI: 10.1021/bc5005747
      29
      Effect of Attachment Site on Stability of Cleavable Antibody Drug Conjugates
      Dorywalska, Magdalena; Strop, Pavel; Melton-Witt, Jody A.; Hasa-Moreno, Adela; Farias, Santiago E.; Galindo Casas, Meritxell; Delaria, Kathy; Lui, Victor; Poulsen, Kris; Loo, Carole; Krimm, Stellanie; Bolton, Gary; Moine, Ludivine; Dushin, Russell; Tran, Thomas-Toan; Liu, Shu-Hui; Rickert, Mathias; Foletti, Davide; Shelton, David L.; Pons, Jaume; Rajpal, Arvind
      Bioconjugate Chemistry (2015), 26 (4), 650-659CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      The systemic stability of the antibody-drug linker is crucial for delivery of an intact antibody-drug conjugate (ADC) to target-expressing tumors. Linkers stable in circulation but readily processed in the target cell are necessary for both safety and potency of the delivered conjugate. Here, we report a range of stabilities for an auristatin-based payload site-specifically attached through a cleavable valine-citrulline-p-aminobenzylcarbamate (VC-PABC) linker across various sites on an antibody. We demonstrate that the conjugation site plays an important role in detg. VC-PABC linker stability in mouse plasma, and that the stability of the linker pos. correlates with ADC cytotoxic potency both in vitro and in vivo. Furthermore, we show that the VC-PABC cleavage in mouse plasma is not mediated by Cathepsin B, the protease thought to be primarily responsible for linker processing in the lysosomal degrdn. pathway. Although the VC-PABC cleavage is not detected in primate plasma in vitro, linker stabilization in the mouse is an essential prerequisite for designing successful efficacy and safety studies in rodents during preclin. stages of ADC programs. The divergence of linker metab. in mouse plasma and its intracellular cleavage offers an opportunity for linker optimization in the circulation without compromising its efficient payload release in the target cell.
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    30. 30
      Chari, R. V., Miller, M. L., and Widdison, W. C. (2014) Antibody-drug conjugates: an emerging concept in cancer therapy Angew. Chem., Int. Ed. 53, 3796– 827 DOI: 10.1002/anie.201307628
      30
      Antibody-Drug Conjugates: An Emerging Concept in Cancer Therapy
      Chari, Ravi V. J.; Miller, Michael L.; Widdison, Wayne C.
      Angewandte Chemie, International Edition (2014), 53 (15), 3796-3827CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody-drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compd. selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado-trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first-generation ADCs have led to improvements in every aspect of this technol., i.e., the antibody, the cytotoxic compd., and the linker connecting them, leading to the current successes. The design of ADCs currently in clin. development, and results from mechanistic studies and preclin. and clin. evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.
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    31. 31
      Younes, A., Bartlett, N. L., Leonard, J. P., Kennedy, D. A., Lynch, C. M., Sievers, E. L., and Forero-Torres, A. (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas N. Engl. J. Med. 363, 1812– 21 DOI: 10.1056/NEJMoa1002965
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      Brentuximab vedotin (SGN-35) for relapsed Cd30-positive lymphomas
      Younes, Anas; Bartlett, Nancy L.; Leonard, John P.; Kennedy, Dana A.; Lynch, Carmel M.; Sievers, Eric L.; Forero-Torres, Andres
      New England Journal of Medicine (2010), 363 (19), 1812-1821CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
      BACKGROUND: Hodgkin's lymphoma and anaplastic large-cell lymphoma are the two most common tumors expressing CD30. Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity. To enhance the antitumor activity of CD30-directed therapy, the antitubulin agent monomethyl auristatin E (MMAE) was attached to a CD30-specific monoclonal antibody by an enzyme-cleavable linker, producing the antibody-drug conjugate brentuximab vedotin (SGN-35). METHODS: In this phase 1, open-label, multicenter dose-escalation study, we administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg per kg of body wt.) every 3 wk to 45 patients with relapsed or refractory CD30-pos. hematol. Cancers, primarily Hodgkin's lymphoma and anaplastic large-cell lymphoma. Patients had received a median of three previous chemotherapy regimens (range, one to seven), and 73% had undergone autologous stem-cell transplantation. RESULTS: The max. tolerated dose was 1.8 mg per kg, administered every 3 wk. Objective responses, including 11 complete remissions, were obsd. in 17 patients. Of 12 patients who received the 1.8-mg-per-kilogram dose, 6 (50%) had an objective response. The median duration of response was at least 9.7 mo. Tumor regression was obsd. in 36 of 42 patients who could be evaluated (86%). The most common adverse events were fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. CONCLUSIONS: Brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-pos. lymphomas in this phase 1 study. Treatment was assocd. primarily with grade 1 or 2 (mild-to-moderate) toxic effects.
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    32. 32
      Verma, S., Miles, D., Gianni, L., Krop, I. E., Welslau, M., Baselga, J., Pegram, M., Oh, D. Y., Dieras, V., and Guardino, E. 2012, Trastuzumab emtansine for HER2-positive advanced breast cancer N. Engl. J. Med. 367, 1783– 91 DOI: 10.1056/NEJMoa1209124
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      Trastuzumab emtansine for HER2-positive advanced breast cancer
      Verma, Sunil; Miles, David; Gianni, Luca; Krop, Ian E.; Welslau, Manfred; Baselga, Jose; Pegram, Mark; Oh, Do-Youn; Dieras, Veronique; Guardino, Ellie; Fang, Liang; Lu, Michael W.; Olsen, Steven; Blackwell, Kim
      New England Journal of Medicine (2012), 367 (19), 1783-1791CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
      BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. METHODS: We randomly assigned patients with HER2-pos. advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. RESULTS: Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 mo with T-DM1 vs. 6.4 mo with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim anal. crossed the stopping boundary for efficacy (30.9 mo vs. 25.1 mo; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all addnl. secondary end points favored T-DM1. Rates of grade 3 or above were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. CONCLUSIONS: T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-pos. advanced breast cancer previously treated with trastuzumab and a taxane.
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