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

Yao, Hang-Ping; Tong, Xiang-Min; Hudson, Rachel; Wang, Ming-Hai

doi:10.1186/s13046-020-01711-x

Journal of Experimental & Clinical Cancer Research

Table 1 Biochemical and biological features of various ADCs specific to MET, RON, and both receptors in different stages of development^a

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

Names of ADCs in development	Produced by institutions	mAbs, target, IgG subtype	Linker properties	mAb binding affinity	Receptor internalization	Drug conjugated	Anticancer activity in cellular models	Therapeutic efficacy in mouse models	Toxicological profiles	Evaluation stages	Ref. cited
ABBV-399 (with MMAE)	AbbVie Oncology CA, USA	ABT-700, MET, human IgG1/κ	Dipeptide, cleavable	Highly specific, ~0.5 nM/L	N/A	MMAE	Highly potent: 0.05 to 18 nM/L for cytotoxicity	Xenografts & PDXs, MET over-expressed & amplified	In primate: bone marrow, liver & digestive	Clinical, Phase II	[57, 65, 83, 84]
TR1801-ADC with PBD	Tanabe Research Laboratories USA, CA, USA	hD12, MET, humanized IgG2	Dipeptide, cleavable	Highly specific, ~0.3 nM/L	30-40% internalized after 24h	PBD	Highly potent: 0.04 to 1.3 nM/L for cytotoxicity	Xenografts & PDXs, MET over-expressed & amplified	In rat, human in progress	Clinical, Phase I	[58, 86]
SHR-A1403 (with SHR152852)	Hengrui Medicine Co Ltd, Shanghai, China	SHR-A1403, MET, humanized IgG2	MC based, noncleavable	Highly specific, ~1.8 nM/L	50-60% internalized within 2h	MMAE	Highly potent: 0.02 to 1.5 nM/L for cell proliferation	Xenografts & PDXs, MET over-expressed & amplified	In primate: bone marrow, liver & digestive	Clinical, Phase I	[59, 60, 85]
P1E2-vc-MMAF	Tanabe Research Laboratories USA CA, USA	P1E2, MET, mouse IgG	Dipeptide, cleavable	Highly specific, ~0.9 nM/L	N/A	MMAF	Highly potent: 0.01 to 0.3 nM/L for cytotoxicity	Xenografts & PDXs, MET over-expressed & amplified	In mouse only	Pre-clinical	[86]
P3D12-vc-MMAF	Tanabe Research Laboratories USA, CA, USA	P3D12, MET, mouse IgG	MC based, noncleavable	Highly specific, ~0.8 nM/L	1.0 μg/ml: ~60% MET internalized within 18h	MMAF	Highly potent: 0.05 to 26 nM/L for cytotoxicity	Xenografts & PDXs, MET over-expressed & amplified	In mouse only	Pre-clinical	[86]
c-Met-IgG-OXA, MetFab-DOX	Nanjing Medical University, Jiangshu, China	Anti-c-Met-IgG, MET, humanized IgG	Unknown	Highly specific, ~13 nM/L	IE50: 50% internalized within 3h	DOX & OXA	Moderately potent: ~11 μM/L for cytotoxicity	Xenografts, MET overexpressed	Unknown	Pre-clinical	[89, 90]
PCM-MET01-MMAE	PCM Targetech, TX, USA	PCMC1D8, MET, humanized IgG1	Dipeptide, cleavable	Highly specific, ~1.6 nM/L	IE50: 50% receptor internalized within 8.2h	MMAE	Highly potent: ~0.6 to 8.0 nM/L for cytotoxicity	Xenografts, MET overexpressed & amplified	In mouse only	Pre-clinical	[78]
HucMET27-DGN549 & HucMET27-DM4	ImmunoGen, Inc., MA, USA	HucMET27, MET humanized IgG	MC or dipeptide, cleavable & noncleavable	specific at nanomolar range	N/A	DGN549 & DM4	Highly potent at nanomolar range for cell killing	Xenografts & PDXs, MET over-expressed & amplified	Unknown	Pre-clinical	[87]
Zt/g4-DM1 & Zt/g4-MMAE	Texas Tech University HSC, TX, USA	Zt/g4, RON, humanized IgG1	MC or dipeptide, cleavable & noncleavable	Highly specific, ~3.0 nM/l	IE50: 50% receptor internalized within 15.3h	DM1, MMAE, & DCM	Highly potent: 0.5 to 25 nM/L for viability, & cell death	Xenografts & PDXs, RON over-expressed	In primates: bone marrow, liver & digestive	Pre-clinical	[61, 62]
PCM5B14-MMAE, PCM5B14-DCM	PCM Targetech, TX, USA	PCM5B14, RON, humanized IgG1	Dipeptide, cleavable	Highly specific, ~2.3 nM/L	IE50: 50% receptor internalized within 9.5h	MMAE &DCM	Highly potent: 0.5 to 25 nM/L for viability, & cell death	Xenografts, RON overexpressed	In primate: bone marrow, liver & digestive	Pre-clinical	[63]
PCMdt-MMAE	PCM Targetech, TX, USA	PCMbs-MR, MET & RON, humanized IgG1	Dipeptide, cleavable	Highly specific, ~2.5 nM/L	IE50: 50% receptor internalized within 15.7h	MMAE	Strong at nM/L in cell cycles, viability, & cell death	Xenografts, MET & RON over- expressed	In mouse only	Pre-clinical	[78]
B10v5x225-H-vc- MMAE	Technische Universität Darmstadt, Germany	B10v5x225-H, MET & EGFR, humanized IgG	Dipeptide, cleavable	Specific but affinity unknown	N/A	MMAE	Highly potent: 0.05 to 18 nM/L for cytotoxicity	Xenografts & PDXs, MET over-expressed & amplified	In mouse only	Pre-clinical	[82]
B10v5x225-M-vc- MMAE	Technische Universität Darmstadt, Germany	B10v5x225-M, MET & EGFR, humanized IgG	Dipeptide, cleavable	Specific but affinity unknown	N/A	MMAE	Highly potent: 0.05 to 18 nM/L for cytotoxicity	Xenografts & PDXs, MET over-expressed & amplified	In mouse only	Pre-clinical	[82]

^aAll information described in the Table 1 is from published articles. ADC Antibody-drug conjugates, DCM Duocarmycin, DGN549 a DNA-alkylating payload indolinobenzodiazepine, DM1 Maytansinoid derivative 1, DM4 Maytansinoid derivative 4, DOX Doxorubicin, EGFR Epidermal growth factor receptor, IE50 Internalization efficacy, MC Maleimidocaproyl, MET Mesenchymal-epithelial transition, MMAE Monomethyl auristatin E, MMAF Monomethyl auristatin F, N/A Not available, PBD, Pyrrolobenzodiazepines, PDX Patient derived tumor xenografts, OXA Oxaliplatin, vc Chemical linker containing Val-Cit structures, SHR15852 A synthetic auristatin analog, RON Recepteur d’Origine nantais

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ISSN: 1756-9966

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