SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression

Abstract

Purpose Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We compared the efficacy of SYD985, (Synthon Biopharmaceuticals BV), a novel HER2-targeting antibody-drug conjugate (ADC), to Trastuzumab emtansine (T-DM1, Genentech-Roche) against primary uterine and ovarian CS. Experimental Design Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification by FISH assays. The in vitro experiments included cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing. In vivo activity was studied in mouse xenograft and patient-derived-xenograft (PDX) models. Results SYD985 and T-DM1 induced similar levels of ADCC against CS cell lines with low and high HER2/neu expression when challanged in the presence of effector cells. In contrast, SYD985 was 7 to 54 fold more potent than T-DM1 in the absence of effector cells. SYD985, unlike T-DM1, was active against CS demonstrating low or heterogeneous HER2/neu expression. Specifically, the mean IC50’s were 0.060 µg/mL and 3.221 µg/mL (p<0.0001) against HER2/neu 0/1+ cell lines and 0.013 µg/mL and 0.096 µg/mL (p<0.0001) against HER2/neu 3+ cell lines for SYD985 vs T-DM1, respectively. Importantly, unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in CS and highly effective against HER2/neu expressing xenografts and PDX. Conclusions SYD985 may represent a novel and highly effective ADC against HER2-expressing CS. Clinical studies with SYD985 in patients harboring chemotherapy-resistant CS with low/moderate and high HER2 expression are warranted.

Molecular variations in uterine carcinosarcomas identify therapeutic opportunities

“…HER2 amplification was only present in three of 33 samples (9%), while other groups have reported overexpression in up to 20% of samples,25 although methods of quantification vary. A recent preclinical study documented efficacy of a novel HER2-targeting antibody drug conjugate in uterine carcinosarcomas in vivo 26…”

Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer

“…Like trastuzumab deruxtecan, SYD985 is also active in cell lines and tumour models expressing low levels of HER2, potentially owing to the bystander effect of its payload, where degradation of the cleavable linker in tumour cells by proteases such as cathepsin B releases the membrane-penetrant payload to passively diffuse to proximal antigen-negative or antigen-low cells. 68 , 69 SYD985 has shown promising efficacy in Phase 1 trials in heavily pre-treated patients with HER2-positive, T-DM1-resistant and HER2-low metastatic breast cancer 70 and is currently undergoing Phase 3 evaluation for HER2-positive, unresectable, locally-advanced or metastatic breast cancer.…”

A radical S-adenosyl-L-methionine enzyme and a methyltransferase catalyze cyclopropane formation in natural product biosynthesis

“…Thus, these compounds have attracted continuing concerns for chemical, biological, and pharmaceutical studies 24 , 25 . Currently, a series of analogues of 1 and the duocarmycins have been chemically developed for the use in targeted tumor therapies with two members (SYD985 and MDX-1203) into Phase I clinical trials 26 – 28 .

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