AJICAP™：位置特異的ADCの次世代化学合成法の開発

抄録

Antibody-drug conjugates (ADCs) have become a major class of cancer biopharmaceuticals and traditional ADCs have a stochastic distribution of cytotoxic drugs linked across several different sites of the antibody. The heterogeneous nature of resulting stochastic ADCs can cause diminished efficacy and increased toxicity, thus limiting the corresponding therapeutic index. To improve on traditional ADC technology, we developed and report here a novel chemical conjugation platform termed “AJICAP™” for the site-specific modification of native antibodies through the use of a class of IgG Fc-affinity reagents. Site-specific installation of thiol functional groups to well-defined lysine residues in IgGs followed by conjugation to these newly installed thiols with cytotoxic payloads was efficiently conducted to generate AJICAP™-ADCs. Conjugation site location was confirmed by peptide mapping and Q-TOFMS analysis showed that the Drug/Antibody Ratio (DAR) was approximately two. Several xenograft in vivo efficacy studies were conducted and indicated the AJICAP™-ADCs display significant tumor inhibition comparable to Kadcyla^®. Furthermore, a rat pharmacokinetic analysis and toxicology study indicated an enhancement of the maximum tolerated dose, indicating an expansion of the comparative AJICAP™-ADC therapeutic index compared to stochastic technology. AJICAP™ technology is a powerful platform to enable next-generation ADCs through the reduction of heterogeneity and enhanced of therapeutic index.