Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells

Abstract

Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers acquire resistance to EGFR tyrosine kinase inhibitors through multiple mechanisms including c-Met receptor pathway activation. We generated a bispecific antibody targeting EGFR and c-Met (JNJ-61186372) demonstrating anti-tumor activity in wild-type and mutant EGFR settings with c-Met pathway activation. JNJ-61186372 was engineered with low fucosylation (<10 %), resulting in enhanced antibody-dependent cell-mediated cytotoxicity and FcγRIIIa binding. In vitro and in vivo studies with the single-arm EGFR or c-Met versions of JNJ-61186372 identified that the Fc-activity of JNJ-61186372 is mediated by binding of the anti-EGFR arm and required for inhibition of EGFR-driven tumor cells. In a tumor model driven by both EGFR and c-Met, treatment with Fc-silent JNJ-61186372 or with c-Met single-arm antibody reduced tumor growth inhibition compared to treatment with JNJ-61186372, suggesting that the Fc function of JNJ-61186372 is essential for maximal tumor inhibition. Moreover in this same model, downregulation of both EGFR and c-Met receptors was observed upon treatment with Fc-competent JNJ-61186372, suggesting that the Fc interactions are necessary for down-modulation of the receptors in vivo and for efficacy. These Fc-mediated activities, in combination with inhibition of both the EGFR and c-Met signaling pathways, highlight the multiple mechanisms by which JNJ-61186372 combats therapeutic resistance in EGFR mutant patients.

Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance

“…The EGFR/Met bispecific antibody, JNJ-61186372, was produced by Janssen Pharmaceuticals as previously described (24,25). The EGFR tyrosine kinase inhibitor, osimertinib (AZD9291) (26), used for the tumor xenograft studies was produced by Wuxi.…”

“…Bi-specific antibodies present one such approach, and have recently been approved in leukemia, with several other bi-specific antibodies in advanced clinical development (22,23). For NSCLC, the novel bi-specific antibody JNJ-61186372 targeting EGFR and Met was recently reported to be effective in EGFR TKI resistant preclinical models (24,25). However, even in the context of this promising preclinical data, multiple tumor xenografts in mouse models continued to grow out in the presence of JNJ-61186372, suggesting that acquired resistance will most likely represent a clinical challenge, even for bi-specific antibody treatments.…”

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

“… 130 Bispecific antibody with EGFR (GA201) and affinity-matured IGF-1R (R1507) – F13B5 specificities     JNJ-61186372EGFR and c-MetReduced (<10%)CHO cells with low level of fucoseEnhanced xenograft tumor inhibition in nude mouse over control and afucosylated IgG2 isotypeGrugan et al. 109 Bispecific human IgG1     Ifabotuzumab/KB004/IIIA4EPHA3afucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Enhanced tumor growth inhibition over control antibody in DU145 or 22Rv1 xenograft miceVail et al. 132 Humanized IgG1     Bemarituzumab /FPA144FGFR2bafucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Enhanced tumour growth inhibition in FGFR2-overexpressing gastric cancer xenograft mouse model over isotype control(b)Humanized IgG1     Afucosylated TrastuzumabHER2afucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Enhanced tumor growth inhibition over fucosylated trastuzumab in KPL-4 xenografts in human FcγRIIIα miceJunttila et al.…”

“…Antibodies with reduced fucosylation against receptors like EGFR, insulin-like growth factor 1 receptor and c-Met have been generated and tested in murine models. 108-110 In addition to the anti-EGFR antibody imgatuzumab (GA201 or RG7160), bi-specific glycoengineered formats against two different receptors have also been developed 109 110 In xenograft SCID mouse models, these afucosylated antibodies demonstrated enhanced tumor inhibition in vivo , which is probably dependent on their enhanced binding to FcγRIII on various effector cells.…”

Progress of antibody-based inhibitors of the HGF–cMET axis in cancer therapy

“…34 JNJ-61186372 inhibits tumor cell growth by the downregulation of both EGFR and cMET in combination with enhanced antibody-dependent cell-mediated cytotoxicity. 33, 35, 36, 37 Patients with NSCLC with EGFR mutations are being recruited for a phase I clinical study (NCT02609776).…”