[PDF] Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis | Semantic Scholar (2024)

Amivantamab is a bispecific antibody that recognizes epidermal growth factor receptor (EGFR) and MET proto-oncogene and determines antibody dependent cellular cytotoxicity and down regulation of cell surface proteins through internalization of the receptor and trogocytosis.

The drug profile of amivantamab is outlined, compared with EGFR kinase inhibitors under evaluation in EGFR exon 20 insertion mutant NSCLC, and what role MET inhibition plays in toxicity and efficacy and whether dual target inhibition can delay the onset of drug resistance in these cancers is determined.

It is concluded that depleting suppressive cells and targeting tumor vasculature, through administration of afucosylated anti-CD39 antibody and the activation of ADCC, comprises an improved, purinergic system–modulating strategy for cancer therapy.

Amivantamab was the first EGFR/MET bispecific antibody to be approved specifically for EGFR exon20ins where there was an unmet need and is being evaluated in additional settings such as post osimertinib in sensitizing EGFR mutations as well as in MET altered NSCLC.

Evidence is presented that anti-CD47 blocking antibodies improve the antitumor effect of macrophages in RCC, and in combination with VEGFR TKIs, CD47 blockade is a potential therapeutic strategy for patients with RCC.

In vivo tumor models indicated that certain doses of fusion proteins could inhibit the A549 xenograft tumors in NOD SCID mice and investigation of the underlying mechanism revealed that these protein chimeras could induce vacuolation in treated cells, thus interfering with the normal extension and arrangement of microtubules as well as the mitosis, leading to the induction of methuosis-mediated cell death.

In vivo studies demonstrated that HLX07 significantly inhibited the growth of A431, FaDu, NCI-H292, and WiDr tumor cells and synergized them with chemotherapeutics and immune simulator agents such as anti-PD-1 and shows better bioactivity compared to cetuximab in vitro.

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A bispecific EGFR-cMet antibody with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway is engineered, highlighting the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC.

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.

JNJ-372 binds EGFR and cMet to block ligand binding, promote receptor degradation, and trigger antibody-dependent cellular cytotoxicity in models of EGFR-mutated (EGFRm) NSCLC.

The data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors.

It is demonstrated that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcγRIIB.

The combination of bsAb affinity engineering with the concept of toxin conjugation may be a viable route to improve the safety profile of ADCs targeting ubiquitously expressed antigens.

Strategies for enhancing ADCC are discussed and the potential of combination treatments that include US Food and Drug Administration-approved mAbs and immunostimulatory therapeutics are emphasized.

Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

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