SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as the first‐line treatment of non‐small cell lung cancers (NSCLC) harboring EGFR‐activating mutations, but acquired resistance is ubiquitous and needs to be solved urgently. Here, we introduce an effective approach for overcoming resistance to the EGFR‐TKI, AZD9291, in NSCLC cells using SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met)‐targeting antibody‐drug conjugate (ADC) consisting of an anti‐c‐Met monoclonal antibody (c‐Met mAb) conjugated to a microtubule inhibitor. Resistant cells were established by exposing HCC827 to increasing concentrations of EGFR‐TKI. c‐Met was found to be overexpressed in most resistant cells. AZD9291 resistance was partially restored by combination of AZD9291 and crizotinib only in resistant cells overexpressing phospho‐c‐Met, which synergistically inhibited c‐Met‐mediated phosphorylation of the downstream targets ERK1/2 and AKT. In resistant cells overexpressing c‐Met, neither crizotinib nor c‐Met mAb was able to overcome AZD9291 resistance. In contrast, SHR‐A1403 strongly inhibited proliferation of AZD9291‐resistant HCC827 overexpressing c‐Met, regardless of the levels of c‐Met phosphorylation. SHR‐A1403 bound to resistant cells overexpressing c‐Met was internalized into cells and released associated microtubule inhibitor, resulting in cell‐killing activity that was dependent on c‐Met expression levels only, irrespective of the involvement of c‐Met or EGFR signaling in AZD9291 resistance. Consistent with its activity in vitro, SHR‐A1403 significantly inhibited the growth of AZD9291‐resistant HCC827 tumors and caused tumor regression in vivo. Thus, our findings show that SHR‐A1403 efficiently overcomes AZD9291 resistance in cells overexpressing c‐Met, and further indicate that c‐Met expression level is a biomarker predictive of SHR‐A1403 efficacy.

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 ).…”

“… SHR-A1403 : This ADC is formed by humanized anti-MET mAb HTI-1066 (also known as SHR-A1403 mAb, IgG2) with payload SHR152852 using a non-cleavable linker (Fig. 3 ; Table 1 ) [ 59 , 60 ]. The resulting ADC is heterogeneous and currently under phase I clinical trials (NCT03856541).…”

“…The resulting ADC is heterogeneous and currently under phase I clinical trials (NCT03856541). Humanized HTI-1066 binds to MET from human and monkey species with high affinities, interacts at very low affinities with cellular Fc receptors and complement component C1q, and strongly induces MET internalization [ 59 , 60 ]. SHR152852 is a microtubule inhibitor derived from a series of chemically designed auristatin analogs [ 59 , 60 ].…”

“…Humanized HTI-1066 binds to MET from human and monkey species with high affinities, interacts at very low affinities with cellular Fc receptors and complement component C1q, and strongly induces MET internalization [ 59 , 60 ]. SHR152852 is a microtubule inhibitor derived from a series of chemically designed auristatin analogs [ 59 , 60 ]. The rationale to select SHR152852 was to have a payload with reduced cytotoxicity for liver cells in free drug form but sustained activity in the form of an ADC for cancer cell killing [ 59 , 60 ].…”

“…SHR152852 is a microtubule inhibitor derived from a series of chemically designed auristatin analogs [ 59 , 60 ]. The rationale to select SHR152852 was to have a payload with reduced cytotoxicity for liver cells in free drug form but sustained activity in the form of an ADC for cancer cell killing [ 59 , 60 ]. The resulting SHR-A1403 ADC, having a DAR of 2, has a favorable PK profile in animals including the cynomolgus monkey with minimal dissociation in vivo .…”