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Design,Synthesis, and in vitro Evaluation of Multivalent Drug Linkers for High‐Drug‐Load Antibody–Drug Conjugates
Authors:Dr. Bo Chen  Dr. Diego A. Gianolio  Dr. James E. Stefano  Charlene M. Manning  Dr. Richard C. Gregory  Michelle M. Busch  Dr. William H. Brondyk  Dr. Robert J. Miller  Dr. Pradeep K. Dhal
Affiliation:Sanofi Global R&D, Waltham, MA, USA
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. ≈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 monomethyldolastatin 10 (MMAD). The in vitro 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.
Keywords:antibody–  drug conjugates  multivalent drug linkers  polyethylene glycol  trastuzumab
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