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• W3000640916 abstract "NSCLC is the most common form of cancer. Approximately 20% of NSCLC patients have mutations in the growth factor (GF) receptor EGFR. These patients respond to tyrosine kinase inhibitors (TKIs) that target mutant EGFR; however relapse eventually occurs. c-MET is one of the most common GF pathways upregulated in resistant patients. Met amplification is found in 5-10% of tumors that acquire resistance to EGFR TKIs in the first line of treatment and this frequency becomes higher in later lines of treatment. Preclinical studies have shown that co-inhibition of c-MET and EGFR inhibits growth and survival in these resistant tumors. We describe here an unbiased functional screen of bispecific antibodies (bAbs) targeting EGFR and c-MET to select MCLA-129 and its evaluation in an in vivo xenograft NSCLC model. Large collections of common light chain Fab binding ‘arms’ against EGFR and c-MET were derived from immunized MeMo® mice and used in different combinations (based on epitope and sequence diversity) to generate IgG1 Biclonics® bAbs. The panel of > 400 bAbs was screened for proliferation inhibition of the N87 cell line stimulated with EGF and/or HGF. Five bAbs inhibited N87 growth comparable to the combination of cetuximab and a MetMab analog (C+M). Two of the most potent Biclonics® bAbs were selected for further characterization and screened for inhibitory activity in NSCLC cell lines PC-9 and HCC827 that harbour an EGFR exon 19 deletion. The addition of HGF reversed the inhibitory effect of the EGFR TKI erlotinib and gefitinib in both cell lines. Combination of bAbs or C+M with erlotinib or gefinitinib resulted in inhibition of growth and downstream phosphorylation similar to erlotinib treatment without GF addition in both HGF alone or HGF + EGF culture conditions. The best bAb was as potent (PC-9) or more potent (HCC827) than C+M. The lead bAb, MCLA-129 was ADCC enhanced and shown to effectively mediate ADCC against NSCLC cell lines with both high and low affinity FcR bearing effector cells. MCLA-129 was then tested in an genetically engineered immunodeficient xenograft mouse model where endogenous mouse HGF promoter drives the expression of human HGF bypassing the problem of the low affinity binding of mouse HGF for human c-MET. Mice engrafted with HCC827 cells and treated with MCLA-129 (25 mg/kg) displayed significant tumor regression (below baseline) and a much slower tumor regrowth rate upon drug cessation and this activity was enhanced when combined with erlotinib (6mg/kg). This potent therapeutic activity was achieved without the contribution of ADCC and was not observed in mice that received only erlotinib, a bivalent c-MET antagonizing antibody or their combination. To model acquired resistance to EGFR TKI treatment, animals were treated with erlotinib until tumors were >500mm3, MCLA-129 was added to erlotinib in one randomized group. In this group, immediate tumor inhibition was observed, which persisted over the treatment period. In summary, MCLA-129 was synergistic with EGFR targeting TKI’s to reverse c-MET mediated resistance in NSCLC cell lines both in vitro and in vivo. The activity of MCLA-129 was superior to relevant comparator biologics that were combined to inhibit EGFR and c-MET signaling in the absence of functional immunity. These preclinical data suggest MCLA-129 could benefit NSCLC patients that become resistant to EGFR targeted therapies and warrants clinical evaluation. Citation Format: Cecile Geuijen, Mario di Matteo, Tristan Gallenne, Sarah Trusso Cafarello, Roy Nijhuis, Therese Visser, Willem Bartelink, Carina Bartelink-Clements, Berina Eppink, Rinse Klooster, John dekruif, Massimiliano Mazzone, Mark Throsby. Preclinical evaluation of MCLA-129: A bispecific antibody targeting c-MET and EGFR [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-C07. doi:10.1158/1535-7163.TARG-19-LB-C07" @default.
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• W3000640916 date "2019-12-01" @default.
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• W3000640916 title "Abstract LB-C07: Preclinical evaluation of MCLA-129: A bispecific antibody targeting c-MET and EGFR" @default.
• W3000640916 doi "https://doi.org/10.1158/1535-7163.targ-19-lb-c07" @default.
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