Payload diversification: a key step in the development of antibody–drug conjugates

Conilh, Louise; Sadilkova, Lenka; Viricel, Warren; Dumontet, Charles

doi:10.1186/s13045-022-01397-y

Journal of Hematology & Oncology

Table 1 Landscape of topoisomerase 1 inhibitors antibody–drug conjugates

From: Payload diversification: a key step in the development of antibody–drug conjugates

Payload name	ADC name	Antibody	Antibody target	linker	Conjugation site	DAR	Development status	Indication	Last publication date or clinical trial status	Reference
Dxd	DsS8201a, trastuzumab deruxtecan, Enhertu	trastuzumab	HER2	mc-GGFG-AM cleavable	cysteine	8	FDA approved	unresectable or metastatic HER2 + BC, gastric or gastroesophageal carcinoma	N/A	48
	U3-1402, patritumab deruxtecan	patritumab	HER3	mc-GGFG-AM cleavable	cysteine	8	phase II	NSCLC, metastatic colorectal, metastatic BC and BC	Recruiting or active	NCT04479436, NCT03260491, NCT02980341, NCT04619004, NCT04676477, NCT04699630, NCT04610528, NCT0496576
	Ds-1062a, datopotamab deruxtecan	datopotamab	TROP2	mc-GGFG-AM cleavable	cysteine	4	phase III	NSCLC, metastatic lung cancer, TNBC, HR + BC, BC	Recruiting or active	NCT02923115, NCT03742102, NCT04526691, NCT04612751, NCT05104866, NCT03401385, NCT04940325, NCT04656652, NCT04484142, NCT05215340
	Ds-7300a	B7-H3 antibody	B7-H3	mc-GGFG-AM cleavable	cysteine	4	phase I/II	Advanced solid malignant tumors	Recruiting or active	NCT04145622
	Ds-6157a	GPR20 antibody	GPR20	mc-GGFG-AM cleavable	cysteine	8	Phase I	GIST	Recruiting or active	NCT04276415
SN-38	IMMU-132, sacituzumab govitecan, Trodelvy TM	sacituzumab (hRS7)	TROP2	Cleavable CL2A (hydrolyzable)	cysteine	7.6	FDA approved	HER + /HER-Metastatic BC (mTNBC)	N/A	49
	IMMU-130	labetuzumab (hMN-14)	CEACAM5	Cleavable CL2A (pH-sensitive)	cysteine	7.6	Phase II (withdrawn)	Solid tumors (metastatic colorectal; colon cancer; rectal cancer)	2020 (Phase II withdrawal)	NCT01270698, NCT01605318, NCT01915472
	*IMMU-140*	*IMMU–112 (hL243)*	*HLA-DR*	*Cleavable CL2A (pH-sensitive)*	*cysteine*	*6.1*	*late preclinical*	*ALL, CLL, MM, AML, DLBCL, HL and melanoma*	*2018*	87
		*Epratuzumab (hLL2)*	*CD22*	*Cleavable CL2A (pH-sensitive) or CL2E (cathepsin cleavable)*	*cysteine*	6	*preclinical*	*B cell malignancy, Lymphoma and leukemia*	*2012*	88
		*Veltuzumab*	*CD20*	*Cleavable CL2A (pH-sensitive) or CL2E (cathepsin cleavable)*	*cysteine*	6	*preclinical*	*B cell malignancy*	*2012*	88
		*Milatuzumab*	*CD74*	*Cleavable CL2A (pH-sensitive) or CL2E (cathepsin cleavable)*	*cysteine*	*6.5–6.6*	*Preclinical*	*solid cancers (and lymphoma)*	*2013*	89
		*Trastuzumab*	*HER2*	*ester bond or carbonate cleavable (± PEG4)*	*Cysteine*	*3.2–3.7*	*preclinical*	*ovarian*	*2015*	90
		*A7R*	*IL-7R*	*Carbamate bond + PEG12*	*Cysteine*	*4 to 6*	*late preclinical*	*IL-7R + Lymphoid malignancies, autoimmune diseases, metastatic solid tumors*	*2018*	93
		*rituximab*	*CD20*	*Carbamate or ester cleavable + PEG27*	*cysteine*	7	*preclinical*	*Lymphoma*	*2013*	91
		*B8-4*	*EpCam*	*Carbamate or ester cleavable + PEG27*	*cysteine*	*8.5*	*preclinical*	*Pancreatic cancer*	*2013*	91
		*35–4*	*Collagen-4*	*Carbamate or ester cleavable + PEG27*	*cysteine*	*7.5*	*preclinical*	*hypovascular stroma-rich tumor (pancreatic)*	*2013*	91
AZ'0132 (exatecan derivative)	AZD8205	B7-H4 antibody	n.d	n.d	n.d	8	Phase I/Phase II	breast, ovarian and endometrial cancers and cholangiocarcinoma	2021	NCT05123482, 69
KL610023 (belotecan derivative)	SKB-264	n.d	TROP2	n.d	n.d	7.4	Phase I/II	ovarian epithelial and breast cancer, gastric and urothelial carcinoma, NSCLC, SCLC	Recruiting or active	NCT04152499
Exatecan mesylate		*Trastuzumab*	*HER2*	*cleavable glucuronide + PSARLink*	*cysteine*	8	*preclinical*	*HER2 + solid tumors*	*2021*	36
	*PRO1184*	*Fra antibody*	*Fra*	*hydrophilic protease cleavable*	*cysteine*	8	*late preclinical*	*NSCLC, ovarian*	*2022*	77
	*PRO1102*	*Trastuzumab*	*HER2*	*hydrophilic protease cleavable*	*cysteine*	8	*POC*		*2022*	76
	*PRO1160*	*CD70 antibody*	*CD70*	*hydrophilic protease cleavable*	*cysteine*	8	*preclinical*		*2022*	78
7-n-butyl-10-amino-CPT		*cAC10*	*CD30*	*mc-Val-cit-PAB or glucuronide cleavable linkers*	*cysteine*	*4 to 8*	*preclinical*	*hematologic malignancies*	*2009*	94
		*h1F6*	*CD70*	*mc-Val-cit-PAB or glucuronide cleavable linkers*	*cysteine*	*4 to 8*	*preclinical*	*hematologic malignancies and renal cell carcinoma*	*2009*	94
		*cBR96*	*LeY*	*mc-Val-cit-PAB or glucuronide cleavable linkers*	*cysteine*	*4 to 8*	*preclinical*	*carcinoma*	*2009*	94
7-n-butyl-9-amino-10, 11-MDO-CPT		*cAC10*	*CD30*	*mc-Val-cit-PAB or glucuronide cleavable linkers*	*cysteine*	*4 to 8*	*preclinical*	*hematologic malignancies*	*2009*	94
		*h1F6*	*CD70*	*mc-Val-cit-PAB or glucuronide cleavable linkers*	*cysteine*	*4 to 8*	*preclinical*	*hematologic malignancies and renal cell carcinoma*	*2009*	94
		*cBR96*	*LeY*	*mc-Val-cit-PAB or glucuronide cleavable linkers*	*cysteine*	*4 to 8*	*preclinical*	*carcinoma*	*2009*	94
CPT		*trastuzumab*	*HER2*	*Pt–PEG, ester cleavage*	*cysteine*	*2.5–4*	*POC*	*Solid tumors*	*2017*	95
		*cetuximab*	*EGFR*	*Pt–PEG, ester cleavage*	*cysteine*	*2.5–4*	*POC*	*Solid tumors*	*2017*	95
		*rituximab*	*CD20*	*Pt–PEG, ester cleavage*	*cysteine*	*2.5–4*	*POC*	*N/A*	*2017*	95
AMDCPT	*SGN-CD30c*	*cAC10*	*CD30*	*maleimidopropionyl-PEG7-valine-lysine-glycine*	*cysteine*	8	*late preclinical*	*Relapse and refractory lymphoma*	*2020*	*97, 98*
		*cAC10*	*CD30*	*val-lysine-glycine tripeptide ± PEG4 or PEG8*	*cysteine*	8	*preclinical*	*lymphoma*	*2021*	96
other CPT derivative			*EGFR or Fra*	*mc-AAA-AM cleavable ± polyhydroxyl moiety*	*cysteine*	*6.4–7.5*	*preclinical*	*solid tumors*	*2019*	79

FDA-approved (Bold), clinically evaluated (Italic) and preclinically developed ADCs are described. ADC Antibody–drug conjugate, DAR drug-to-antibody ratio, FDA Food and Drug Administration

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