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

Emilia Rabia (1) , Véronique Garambois (1) , Christine Dhommée (2) , Christel Larbouret (1) , Laurie Lajoie (2) , Yoan Buscail (1, 3) , Gabriel Jimenez-Dominguez (1) , Sylvie Choblet-Thery (3, 4) , Emmanuelle Liaudet-Coopman (1) , Martine Cerutti (3, 4) , Marta Jarlier (5) , Patrice Ravel (1) , Laurent Gros (1) , Nelly Pirot (1, 3) , Gilles Thibault (2) , Eugene Zhukovsky (6) , Pierre-Emmanuel Gérard (6) , André Pèlegrin (1) , Jacques Colinge (1) , Thierry Chardès (1)

1 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
2 GICC EA 7501 - Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...]
3 BCM - BioCampus
4 Baculovirus et Thérapie
5 ICM - UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle
6 Biomunex Pharmaceuticals

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.

Mots clés: ErbB HER systems biology antibody bispecific pancreatic cancer ADCC CDC signaling phosphoproteome; ErbB; HER; systems biology; antibody; bispecific; pancreatic cancer; ADCC; CDC; signaling; phosphoproteome

Domaines: Sciences du Vivant [q-bio]

Emilia Rabia, Véronique Garambois, Christine Dhommée, Christel Larbouret, Laurie Lajoie, et al.. Design and selection of optimal ErbB-targeting bispecific antibodies in pancreatic cancer. Frontiers in Immunology, 2023, 14, ⟨10.3389/fimmu.2023.1168444⟩. ⟨hal-04102843v1⟩