Non-small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies. In NSCLC tumor models driven by EGFR and/or cMet, JNJ-61186372 treatment resulted in tumor regression through inhibition of signaling/ receptor downmodulation and Fc-driven effector interactions. Complete and durable regression of human lung xenograft tumors was observed with the combination of JNJ-61186372 and a third-generation EGFR TKI. Interestingly, treatment of cynomolgus monkeys with JNJ-61186372 resulted in no major toxicities, including absence of skin rash observed with other EGFR-directed agents. These results highlight the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC.Cancer Res; 76(13); 3942-53. Ó2016 AACR.
Small molecule inhibitors targeting mutant epidermal growth factor receptor (EGFR) are standard of care in non-small cell lung cancer (NSCLC), but acquired resistance invariably develops through mutations in EGFR or through activation of compensatory pathways such as cMet. Amivantamab (JNJ-61186372) is an anti-EGFR and anti-cMet bispecific low fucose antibody with enhanced Fc function designed to treat tumors driven by activated EGFR and/or cMet signaling. Potent in vivo anti-tumor efficacy is observed upon amivantamab treatment of human tumor xenograft models driven by mutant activated EGFR and this activity is associated with receptor downregulation. Despite these robust anti-tumor responses in vivo, limited antiproliferative effects and EGFR/cMet receptor downregulation by amivantamab were observed in vitro. Interestingly, in vitro addition of isolated human immune cells notably enhanced amivantamab-mediated EGFR and cMet downregulation leading to antibody dose-dependent cancer cell killing. Through a comprehensive assessment of the Fc-mediated effector functions, we demonstrate that monocytes and/or macrophages, through trogocytosis, are necessary and sufficient for Fc interaction-mediated EGFR/cMet downmodulation and are required for in vivo anti-tumor efficacy. Collectively, our findings represent a novel Fc-dependent macrophagemediated anti-tumor mechanism of amivantamab and highlight trogocytosis as an important mechanism of action to exploit in designing new antibody-based cancer therapies.
Background: Cancer cells express surface antigens at different levels from normal cells.Results: Differences in EGFR and c-MET receptor density levels influenced the in vitro activity of an EGFR × c-MET bispecific antibody.Conclusion: Consideration of target expression levels is important for bispecific design.Significance: In addition to multiple pathway targeting, the unique avidity of bispecific antibodies contributes to their promise for cancer therapy.
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.
In April 1987, a census of children dependent on medical technology was carried out in Massachusetts to determine the one-month point prevalence. All medical and educational providers in the state who were likely to interact with such children were contacted and asked to complete a two-sided data form on youngsters (aged 3 months to 18 years) with tracheostomies, supplementary oxygen, respirators, suctioning, gastric feeding, central venous lines, ostomies, ureteral diversion, urethral catheterization and dialysis. Nearly 1250 children were found meeting these criteria. Capture-recapture analysis set the lower bound for technology dependence at 0.08% of the state's children. An analysis of the organ systems involved showed that 57% of the children had neurologic involvement—13% multisystem, 7% gastrointestinal-metabolic, 4% renal-genitourinary, and 3% musculoskeletal. Less than 1% of the children were reported as having immunologic or "other" disorders. Review of putative etiologies indicated that 45% of the children had congenital anomalies, 33% chronic medical diseases, 9% perinatal conditions, 7% hereditary-genetic disorders, 5% injuries, 2% infections, and 3% "other." The substantial prevalence of technology dependency among children creates challenges at the social, economic, and policymaking levels. It will be important to carry out systematic reporting and monitoring activities throughout time and across sites. This census is an example of one such statewide effort.
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