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Design and selection of optimal ErbB-targeting bispecific antibodies in pancreatic cancer
Emilia Rabia1, Véronique Garambois1, Christine Dhommée2
1IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France.
Abstract:
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.
Insights
Researchers developed novel bispecific antibodies targeting the ErbB family (EGFR, HER2, HER3) to improve pancreatic cancer treatment. These new antibodies demonstrated significant tumor growth reduction in preclinical models, offering a promising therapeutic advancement.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- The ErbB family of receptor tyrosine kinases are key targets in pancreatic cancer therapy.
- Current treatments targeting ErbB receptors show limitations including resistance, toxicity, and insufficient efficacy.
- Novel therapeutic strategies are needed to overcome these challenges in pancreatic cancer treatment.
Purpose of the Study:
- To generate and evaluate novel bispecific antibodies targeting multiple ErbB family members (EGFR, HER2, HER3) using the BiXAb™ platform.
- To compare the efficacy of bispecific antibodies against single antibodies and antibody combinations in preclinical pancreatic cancer models.
- To identify potent bispecific antibodies for improved pancreatic cancer therapy.
Main Methods:
- Generation of bispecific antibodies targeting rational epitope combinations of EGFR, HER2, and HER3 using the BiXAb™ tetravalent format.
- Screening of bispecific antibodies measuring receptor binding, intracellular signaling, cell proliferation, apoptosis, and immune engagement (ADCC, CDC).
- In vivo testing of lead bispecific antibody candidates in preclinical mouse models of pancreatic cancer.
Main Results:
- Thirty novel bispecific antibodies (BiXAbs™) were generated and screened.
- Three lead candidates (3Patri-1Cetu-Fc, 3Patri-1Matu-Fc, 3Patri-2Trastu-Fc) demonstrated superior efficacy.
- In vivo studies showed deep tumor penetration and significant tumor growth reduction in pancreatic cancer models.
Conclusions:
- Bispecific antibodies targeting the ErbB family, generated via the BiXAb™ platform, show significant potential for pancreatic cancer treatment.
- This semi-rational/semi-empirical approach, incorporating immunological assays, is effective for identifying potent bispecific antibodies.
- The developed bispecific antibodies represent a promising new therapeutic strategy for pancreatic cancer, addressing limitations of current treatments.
