Design and selection of optimal ErbB-targeting bispecific antibodies in pancreatic cancer.

The ErbB family of receptor tyrosine kinases is a primary target for small molecules and antibodies for pancreatic cancer treatment. Nonetheless, the current treatments for this tumor are not optimal due to lack of efficacy, resistance, or toxicity. Here, using the novel BiXAb™ tetravalent format platform, we generated bispecific antibodies against EGFR, HER2, or HER3 by considering rational epitope combinations. We then screened these bispecific antibodies and compared them with the parental single antibodies and antibody pair combinations. The screen readouts included measuring binding to the cognate receptors (mono and bispecificity), intracellular phosphorylation signaling, cell proliferation, apoptosis and receptor expression, and also immune system engagement assays (antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity). Among the 30 BiXAbs™ tested, we selected 3Patri-1Cetu-Fc, 3Patri-1Matu-Fc and 3Patri-2Trastu-Fc as lead candidates. The in vivo testing of these three highly efficient bispecific antibodies against EGFR and HER2 or HER3 in pre-clinical mouse models of pancreatic cancer showed deep antibody penetration in these dense tumors and robust tumor growth reduction. Application of such semi-rational/semi-empirical approach, which includes various immunological assays to compare pre-selected antibodies and their combinations with bispecific antibodies, represents the first attempt to identify potent bispecific antibodies against ErbB family members in pancreatic cancer.
Competing Interests: Authors EAZ and P-EG were employed by company Biomunex Pharmaceuticals. AP and CL report a patent regarding a combination of anti-HER2 and anti-EGFR antibodies PCT/EP2009/012133. AP, CL, P-EG and EAZ report a patent regarding anti-EGFR/HER2 bispecific antibodies WO2017/186950. MC and SC-T report a patent regarding multi-specific antibodies WO2013/005194. P-EG and EAZ report a patent regarding polypeptide linkers and stable multi-specific antibodies WO2018/127608, WO2018/178101. One patent is pending regarding this work application number EP22305242.4. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Rabia, Garambois, Dhommée, Larbouret, Lajoie, Buscail, Jimenez-Dominguez, Choblet-Thery, Liaudet-Coopman, Cerutti, Jarlier, Ravel, Gros, Pirot, Thibault, Zhukovsky, Gérard, Pèlegrin, Colinge and Chardès.)