ThioMabs: improving safety abd retaining efficacy of antibody drug conjugates

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 918 Antibody drug conjugates (ADCs) are a promising technology for specifically targeting cytotoxic agents to tumor cells. The current method for preparation of ADCs involves the usage of either lysine residues or cysteine residues involved in inter-chain disulfide bonds. Either method results in a heterogeneous population and inconsistent preparation, thereby posing a manufacturing challenge to produce ADCs for therapeutic utility. We have developed a novel robust biochemical assay (PHESELECTOR) to screen reactive thiols on antibody surface with an objective of utilizing these thiol groups for site-specific conjugation of cytotoxic drugs. We have screened and identified several potential ThioMab variants to conjugate cytotoxic drugs to either light or heavy chain (Fab or Fc region). These ThioMabs can then be derivatized through the reactive thiol group of engineered cysteine to obtain ADCs with defined number of drugs (~2 drugs/ab). A number of ThioMab-ADCs were produced and tested in both efficacy and toxicity models. The efficacy of the ThioMab-ADCs is equal if not superior to ADCs produced by the conventional method. Surprisingly, the safety of these conjugates is considerably better than that observed with the conventional ADCs. Therefore, ThioMab technology provides a unique advantage over conventional ADCs to overcome unresolved manufacturing challenges and offers a solution to potential ADC toxicity issues.