SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression

Abstract

Background Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. Less than 10% of EOC demonstrate HER2/neu 3+ receptor over-expression. However, moderate to low (ie, 2+ and 1+) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. Methods The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts Results SYD985 and T-DM1 induced similar ADCC in the presence of peripheral blood lymphocytes (PBL) against EOC cell lines with differential HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1 (p<0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells when admixed with HER2/neu 3+ EOC cells. In vivo studies confirmed that SYD985 is significantly more active than T-DM1 against HER2/neu 3+ EOC xenografts. Conclusions SYD985 is a novel ADC with remarkable activity against EOC with strong (3+) as well as moderate to low (i.e., 2+ and 1+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression.

Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study

“…14 Trastuzumab duocarmazine has shown encouraging preclinical antitumour activity in breast, ovarian, and other cancers with varying (low to high) HER2 expression and was more potent than trastuzumab emtansine. 12,15,16 In this first-in-human study, we assessed the safety, pharmacokinetics, and preliminary antitumour activity of trastuzumab duocarmazine in patients with locally advanced or metastatic solid tumours.…”

Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment

“…SYD985 induced potent antitumor effects in high HER2 expression (3+) or low expression (2+, 1+) in vitro and in vivo, while T-DM1 only showed high antitumor activity in HER2 3+ tumor cell lines and patient-derived xenograft (PDX) models. This phenomenon has been observed in HER2 positive uterine and ovarian carcinosarcoma [ 90 ], epithelial ovarian carcinoma [ 91 ], uterine serous carcinoma [ 92 ] and breast cancer [ 93 ]. DS-8201a contains an anti-HER2 antibody and a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd).…”

Antibody Conjugates-Recent Advances and Future Innovations

“…Emerging literature suggests that the antibody internalization and delivery of the toxic drug to the target cells serves as the primary mechanism of action for ADCs that is far more efficient than ADCC and Antibody-Dependent Cellular Phagocytosis (ADCP). For example, trastuzumab-DM1, SYD985, and DS-8201a all target HER2 and have shown similar ADCC activity as trastuzumab but they have demonstrated dramatically more anti-tumor activity than trastuzumab [26][27][28][29][30][31]. The anti-Trop-2 ADC IMMU-132 represents a more striking case as this ADC lost 60%-70% of the ADCC activity compared with the unconjugated mAb upon the conjugation of SN38 [32].…”