Abstract
cMet is a well‐characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody–drug conjugates (ADCs). However, the clinical benefit from cMet‐targeted therapy has been limited. We developed a novel cMet‐targeted ‘third‐generation’ ADC, TR1801‐ADC, that was optimized at different levels including specificity, stability, toxin–linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site‐specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin–linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet‐expressing cell lines but also in medium‐to‐low cMet cell lines (40 000–90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low–medium cMet expression were also very responsive to TR1801‐ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801‐ADC had excellent efficacy with significant antitumor activity in 90% of tested patient‐derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single‐dose administration. Altogether, TR1801‐ADC is a new generation cMet ADC with best‐in‐class preclinical efficacy and good tolerability in rats.
Highlights
Antibody–drug conjugates (ADCs) with over 40 years of research are a promising and fast-growing class of targeted anticancer immunotherapies
The mouse, anti-human cMet antibody P3D12 was selected as the lead antibody because of its high-affinity binding to humans and cynomolgus monkey (0.8 nM kilo Dalton (kD)), and rat cMet (15.6 nM kD) (Table S2), which allowed to investigate the tolerability of ADCs in another species besides nonhuman primates
The humanization of P3D12 had no negative impact on affinity (0.26 nM kD for human cMet, 7 nM kD for rat cMet), internalization, or nonagonist activity compared to the parental mouse antibody (Fig. S1, Table S2)
Summary
Antibody–drug conjugates (ADCs) with over 40 years of research are a promising and fast-growing class of targeted anticancer immunotherapies. These agents combine the specificity of antibodies with the potency of chemotherapeutics by attaching highly cytotoxic payload–linkers covalently to monoclonal antibodies (Mukherjee et al, 2019). Aberrant cMet expression or constitutive activation of the cMet signaling pathway due to amplification, overexpression of its ligand HGF, and mutation in MET is seen in many human tumor types and is the rationale for developing cMet-targeting therapeutics (Gherardi et al, 2012). Many small molecule cMet inhibitors and pathway-inhibiting biologics were developed over the last decade with limited or no clinical success (Puccini et al, 2019). Novel cMet-targeting therapies, such as ADCs, are in development, which are independent of MET amplification status and target any cMet-overexpressing cancer (Wang et al, 2017; Yang et al, 2019)
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