Acquired Resistance to a MET Antibody In Vivo Can Be Overcome by the MET Antibody Mixture Sym015

Abstract

Failure of clinical trials due to development of resistance to MET-targeting therapeutic agents is an emerging problem. Mechanisms of acquired resistance to MET tyrosine kinase inhibitors are well described, whereas characterization of mechanisms of resistance toward MET-targeting antibodies is limited. This study investigated mechanisms underlying resistance to two antibody therapeutics currently in clinical development: an analogue of the MET-targeting antibody emibetuzumab and Sym015, a mixture of two antibodies targeting nonoverlapping epitopes of MET. Upon long-term treatment of a -amplified gastric cancer xenograft model (SNU-5), emibetuzumab-resistant, but not Sym015-resistant, tumors emerged. Resistant tumors were isolated and used to establish resistant cell lines. Characterization of both tumors and cell lines using extensive protein and signaling pathway activation mapping along with next-generation sequencing revealed two distinct resistance profiles, one involving loss and the other involving activation of the PI3K pathway, likely via and copy number gains. loss left one model unaffected by PI3K/AKT targeting but sensitive to mTOR targeting, while the PI3K pathway-activated model was partly sensitive to targeting of multiple PI3K pathway proteins. Importantly, both resistant models were sensitive to treatment with Sym015 due to antibody-dependent cellular cytotoxicity-mediated tumor growth inhibition, MET degradation, and signaling inhibition. Taken together, our data provide key insights into potential mechanisms of resistance to a single MET-targeting antibody, demonstrate superiority of Sym015 in preventing acquired resistance, and confirm Sym015 antitumor activity in tumors resistant to a single MET antibody. .

Improving Biologics’ Effectiveness in Clinical Oncology: From the Combination of Two Monoclonal Antibodies to Oligoclonal Antibody Mixtures

“…For instance, homo-combinations of antibodies against epidermal growth factor receptor (EGFR) [ 1 , 2 , 3 , 4 , 5 ], human epidermal growth factor receptor-2 (HER2) [ 6 , 7 , 8 , 9 ] or hepatocyte growth factor (HGF) receptor (i.e., cMET) [ 10 , 11 ] induce synergistic anti-tumor activity due to accelerated degradation of the targeted receptors and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) ( Figure 1 ). Moreover, these antibody combinations bypass the resistance to treatment induced by monotherapy with cetuximab (anti-EGFR mAb) in colorectal cancer [ 12 ] and with an anti-cMET antibody in gastric cancer [ 13 ]. They also maintain anti-tumor activity despite the presence of EGFR extracellular domain mutations that might impair antibody binding [ 14 ].…”

“…For instance, a controlled mixture of 25 anti-rhesus D antibodies (rozrolimupab or Sym001 [ 90 ]) was produced and tested in a phase II trial in patients with thrombocytopenic purpura [ 50 ]. Moreover, a mixture of two anti-cMET antibodies (1:1 stoichiometry; Sym015 [ 10 , 11 , 13 ]) was assessed in cMET-amplified tumors (phase II trial), and an oligoclonal mixture of two anti-EGFR antibodies, two anti-HER2 antibodies and two anti-HER3 antibodies (PanHER or Sym013 [ 12 , 30 , 31 , 32 , 91 , 92 , 93 ]) in epithelial cancers (phase I trials).…”

Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement

“…Moreover, dysfunction of the PI3K pathway is linked to resistance to anti-MET antibodies. Especially, Pollmann et al (2018) identified two potential mechanisms of resistance, both involving PI3K pathway activation, according to their long-term in vivo models of either acquired resistance to the MET-targeting antibody emibetuzumab due to PTEN loss or increased receptor tyrosine kinase activation through increased MYC and ERBB3 copy numbers. Furthermore, Sym015, a mixture of two monoclonal antibodies that bind to non-overlapping MET epitopes, effectively prevents or reduces these resistances due to its broader mechanism of action (Kim et al, 2019).…”

“…PIM 1/3 upregulation is associated with acquired resistance to MET inhibitors. PIM kinases mediate resistance to MET inhibitors through the control of cap-independent Bcl-2 translation (Pollmann et al, 2018). Indeed, Henry et al (2016) demonstrated that resistance to savolitinib (a small-molecule inhibitor of MET) could be mediated by PIM kinase signaling, and they showed PIM inhibition restores savolitinib sensitivity in vitro and in vivo (An et al, 2015).…”

Imiter la réponse immunitaire humorale polyclonale

“…Ainsi, des homo-combinaisons d'anticorps anti-EGFR (epidermal growth factor receptor) [1], anti-HER2 (human epidermal growth factor receptor-2) [2] ou anti-cMET (ou hepatocyte growth factor [HGF] receptor) [3] induisent une activité anti-tumorale synergique due à l'accélération de la dégradation des récepteurs ciblés et à une cytotoxicité à médiation cellulaire dépendant des anticorps (ADCC) renforcée (Figure 1). Ces combinaisons permettent de contrer la résistance au traitement provoquée par une monothérapie anti-EGFR dans le cancer colorectal [4], ou anti-cMET dans le cancer gastrique [5], et de maintenir une activité anti-tumorale malgré la présence de mutations des domaines extracellulaires de ces récepteurs [6]. Dès 2007, notre équipe à l'institut de recherche en cancérologie de Montpellier [7], démontrait que l'hétéro-combinaison d'anticorps anti-EGFR/ anti-HER2 engageant des épitopes distincts sur ces deux récepteurs collaborant fonctionnellement, induisait une synergie anti-tumorale en favorisant l'ADCC, la diminution de l'expression de ces récepteurs et la formation des homodimères, mais aussi en inhibant les voies de signalisation intracellulaires [8].…”