TR1801‐ADC: a highly potent cMet antibody–drug conjugate with high activity in patient‐derived xenograft models of solid tumors

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.

Antibody–Drug Conjugates for Cancer Therapy

“…Val-Cit is more stable in the plasma due to the presence of protease inhibitors than acid-based linkers, but can still be rapidly hydrolysed by lysosomal enzyme cathepsin B once internalized [ 55 ]. Another protease-cleavable valine-alanine (Val-Ala) linker has been used for multiple ADCs, including TR1801 where PBD is conjugated to an anti-cMET antibody [ 59 ]. Lastly, glutathione-sensitive disulfide linkers are commonly used in ADC design.…”

MET and RON receptor tyrosine kinases in colorectal adenocarcinoma: molecular features as drug targets and antibody-drug conjugates for therapy

“…At present, seven ADCs including ado-trastuzumab emtansine, brentuximab vedotin, and sacituzumab govitecan have been approved for clinical application ( www.fda.gov ). Since 2013, several anti-MET mAbs including ABT-700, P3D12, and HTI-1066 have been selected for drug conjugation, resulting in several anti-MET ADCs, such as telisotuzumab vedotin (ABBV-399) [ 57 ], TR1801-ADC [ 58 ], and SHR-A1403 [ 59 , 60 ] (Fig. 3 ; Table 1 ).…”

“… TR1801-ADC : This “third generation” ADC is developed through site-specific conjugation of humanized mAb hD12 (IgG2) to PBD toxin-linker tesirine (Fig. 3 ; Table 1 ) [ 58 ]. TR1801 is currently in phase I clinical trials (NCT03859752).…”

“…P3D12 and another anti-MET mAb P1E2 have been conjugated with MMAF to form ADCs P3D12-vc-MMAF and P1E2-vc-MMAF, which have superior potencies in MET amplified and non-amplified cancer models [ 86 ]. Modification of P3D12 through humanization, IgG subclass switching, and site-specific cysteine incorporation results in hD12 for TR1801-ADC development [ 58 ]. The PBD toxin-linker tesirine, known as SG3249 developed by Spirogen, is featured by straightforward cysteine conjugation, good solubility in aqueous/DMSO, and a versatile cleavable linker for delivering PBD DNA cross-linker SG3199 [ 55 ].…”

“…TR1801-ADC is homogeneous with an average DAR of ~ 2.0 [ 58 ]. Toxic studies in rats reveal that TR1801-ADC is well tolerated up to 2 mg/kg with no significant bodyweight reduction or clinical abnormalities [ 58 ].…”