Design, Synthesis, and invitro Evaluation of Multivalent Drug Linkers for High-Drug-Load Antibody-Drug Conjugates
A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. approximate to 4). These...
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Published in | ChemMedChem Vol. 13; no. 8; pp. 790 - 794 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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Wiley
23.04.2018
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Abstract | A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. approximate to 4). These MDLs contain two copies of a cytotoxic agent attached to biocompatible scaffolds composed of a branched peptide core and discrete polyethylene glycol (PEG) chains to enhance solubility and decrease aggregation. These drug linkers produced well-defined ADCs, whose DARs could be accurately determined by LC-MS. Using this approach, ADCs with significantly lower aggregation and higher DAR than those of conventional drug linker design were obtained with highly hydrophobic cytotoxic agents such as monomethyldolastatin10 (MMAD). The invitro potencies of the MDL-derived conjugates matched that of ADCs of similar DAR with conventional linkers, and the potency increased proportionally with drug loading. This approach may provide a means to prepare highly potent ADCs from a broader range of drugs, including those with lower cytotoxicity or poor solubility, which otherwise limits their use for antibody-drug conjugates. This may also provide a means to further improve the potency achievable with cytotoxins currently used in ADCs. |
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AbstractList | A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. approximate to 4). These MDLs contain two copies of a cytotoxic agent attached to biocompatible scaffolds composed of a branched peptide core and discrete polyethylene glycol (PEG) chains to enhance solubility and decrease aggregation. These drug linkers produced well-defined ADCs, whose DARs could be accurately determined by LC-MS. Using this approach, ADCs with significantly lower aggregation and higher DAR than those of conventional drug linker design were obtained with highly hydrophobic cytotoxic agents such as monomethyldolastatin10 (MMAD). The invitro potencies of the MDL-derived conjugates matched that of ADCs of similar DAR with conventional linkers, and the potency increased proportionally with drug loading. This approach may provide a means to prepare highly potent ADCs from a broader range of drugs, including those with lower cytotoxicity or poor solubility, which otherwise limits their use for antibody-drug conjugates. This may also provide a means to further improve the potency achievable with cytotoxins currently used in ADCs. |
Author | Dhal, Pradeep K. Gianolio, Diego A. Miller, Robert J. Busch, Michelle M. Stefano, James E. Chen, Bo Gregory, Richard C. Manning, Charlene M. Brondyk, William H. |
Author_xml | – sequence: 1 givenname: Bo surname: Chen fullname: Chen, Bo organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA – sequence: 2 givenname: Diego A. surname: Gianolio fullname: Gianolio, Diego A. organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA – sequence: 3 givenname: James E. orcidid: 0000-0003-1024-0836 surname: Stefano fullname: Stefano, James E. organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA – sequence: 4 givenname: Charlene M. surname: Manning fullname: Manning, Charlene M. organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA – sequence: 5 givenname: Richard C. surname: Gregory fullname: Gregory, Richard C. organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA – sequence: 6 givenname: Michelle M. surname: Busch fullname: Busch, Michelle M. organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA – sequence: 7 givenname: William H. surname: Brondyk fullname: Brondyk, William H. organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA – sequence: 8 givenname: Robert J. surname: Miller fullname: Miller, Robert J. organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA – sequence: 9 givenname: Pradeep K. surname: Dhal fullname: Dhal, Pradeep K. email: Pradeep.Dhal@sanofi.com organization: Sanofi Global R&D, 153 Second Ave, Waltham, MA 02139 USA |
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Cites_doi | 10.1021/bm049210k 10.1158/0008-5472.CAN-15-0129 10.1038/nbt.3212 10.1158/1535-7163.MCT-16-0343 10.1016/j.bmcl.2014.10.021 10.1021/acs.bioconjchem.5b00223 10.1016/j.xphs.2015.11.015 10.1007/s10875-016-0265-6 10.1038/nrd.2016.268 10.1021/acs.jmedchem.5b00457 10.1007/s00280-012-1925-8 10.1021/jm900899g 10.1038/NNANO.2015.330 10.2174/1568009616666160512144715 |
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Keywords | trastuzumab polyethylene glycol EFFICACY antibody-drug conjugates CANCER CHALLENGES multivalent drug linkers |
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References | Hamblett, KJ (WOS:000224627400036) 2004; 10 Gao, WL (WOS:000378067100002) 2016; 16 Yurkovetskiy, A (WOS:000231899200034) 2005; 6 Gianolio, DA (WOS:000308041100010) 2012; 70 Burke, PJ (WOS:000393695500011) 2017; 16 Bouchard, H (WOS:000345125500002) 2014; 24 Yurkovetskiy, AV (WOS:000359562100017) 2015; 75 Schottler, S (WOS:000373455500015) 2016; 11 King, HD (WOS:000079238300017) 1999; 10 Casi, G (WOS:000366004600001) 2015; 58 Cardillo, TM (WOS:000355053900015) 2015; 26 Turecek, PL (WOS:000381768500010) 2016; 105 Beck, A (WOS:000400370600016) 2017; 16 Schumacher, D (WOS:000398374500016) 2016; 36 Lyon, RP (WOS:000358396100028) 2015; 33 Quiles, S (WOS:000273672100005) 2010; 53 |
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Title | Design, Synthesis, and invitro Evaluation of Multivalent Drug Linkers for High-Drug-Load Antibody-Drug Conjugates |
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