Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis

Abstract

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.

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

“…This is based on the activity of amivantamab in many classes of EGFR mutations (del19, L858R, C797S) including EGFR exon 20 insertions for which amivantamab has received FDA breakthrough therapy designation. [22][23][24][25] Alflutinib (AST2818/Furmonertinib) Alflutinib has a pyridyl ring replacing the phenyl ring and a trifluoroethyl group replacing the methyl group (Fig. 2).…”

Amivantamab in EGFR Exon 20 Insertion–Mutated Non–Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study

“…12,[15][16][17][18][19][20] Amivantamab (JNJ-61186372) is a fully human EGFR-MET bispecific antibody with immune cell-directing activity designed to engage two distinct driver pathways in NSCLC. [21][22][23] By binding to each receptor's extracellular domain, amivantamab can inhibit ligand binding, promote receptor-antibody complex endocytosis and degradation, and induce Fc-dependent trogocytosis by macrophages and antibody-dependent cellular cytotoxicity by natural killer cells. [21][22][23] CHRYSALIS, a first-in-human, phase I dose-escalation, and dose-expansion study (NCT02609776), evaluates the efficacy, safety, and pharmacokinetics of amivantamab in patients with advanced NSCLC.…”

“…[21][22][23] By binding to each receptor's extracellular domain, amivantamab can inhibit ligand binding, promote receptor-antibody complex endocytosis and degradation, and induce Fc-dependent trogocytosis by macrophages and antibody-dependent cellular cytotoxicity by natural killer cells. [21][22][23] CHRYSALIS, a first-in-human, phase I dose-escalation, and dose-expansion study (NCT02609776), evaluates the efficacy, safety, and pharmacokinetics of amivantamab in patients with advanced NSCLC. During the conduct of the study, amivantamab received Breakthrough Therapy Designation on the basis of the preliminary efficacy within the EGFR Exon20ins population, who had previous treatment with platinum-based chemotherapy and for whom limited treatment options were available.…”

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET

“…Inhibition of the cell proliferation in vitro did not reflect all mechanisms of action that may be involved in vivo . The lead bispecific molecule has multiple mechanisms including ADCC, receptor downmodulation, and trogocytosis ( 29 , 42 , 43 ).…”

“…Amivantamab is under clinical development for the treatment of NSCLC (NCT02609776, NCT04077463) and has shown preliminary activity in diverse EGFR-mutated NSCLCs and MET-driven disease ( 46 ). Based on its unique mode of action, which includes induction of trogocytosis from macrophages, ADCC from natural killer cells, and receptor–antibody complex internalization and lysosomal degradation ( 29 , 42 , 43 ), amivantamab may provide significant benefit to patients with NSCLC and other malignancies associated with aberrant EGFR and MET signaling.…”