3914930

Optimisation of a re-bridging platform for homogeneous antibody-drug conjugates (ADCs)

Date
August 14, 2023
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Antibody-drug conjugates (ADCs) are a cutting-edge class of cancer-targeting therapeutic agents that can achieve a wide therapeutic window by combining the selectivity of a monoclonal antibody (mAb) with the antitumor activity of a cytotoxic payload. Current FDA-approved ADCs are prepared from IgG1 or IgG4 antibodies via stochastic modification of surface-exposed lysine residues or site-selective cysteine conjugations. However, current modification technologies fail to successfully modulate the drug-antibody ratio (DAR) to afford homogeneous ADCs without the use of protein engineering. Such highly heterogeneous ADCs, with varying conjugation sites and a distinct distribution of antibody-drug loading, have been shown to negatively impact their safety and efficacy. Herein, we present a method that enables a precise modulation of DAR in integer increments (DAR = 1,2,3 or 4) via click chemistry upon disulfide reduction and re-bridging using a tetradivinylpyrimidine (tetraDVP) platform, which consists of a single linker construct able to simultaneously re-bridge all four disulfide bonds. This novel methodology will enable precise loading of a drug/fluorophore of choice without the need for protein engineering, and has a great potential to lead the next-generation of ADCs.

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