Abstract P4-15-14: Preclinical data of SYD985 support the clinical investigation of this novel anti-HER2 antibody-drug conjugate in breast cancer patients with low levels of HER2 expression

SYD985 is a novel anti-HER2 antibody-drug conjugate (ADC) in development for breast cancer. The ADC consists of three parts: i) the monoclonal antibody trastuzumab, ii) a linker that can be cleaved by tumor-resident proteases at the dipeptide valine-citrulline (vc) motif, and iii) the prodrug seco-DUocarmycin-hydroxyBenzamide-Azaindole. The average ‘drug to antibody ratio’ (DAR) of this ADC, also named trastuzumab vc-seco-DUBA, is ∼2.8. After antibody-mediated binding of SYD985 to its molecular target HER2 on the surface of tumor cells, the ADC is internalized. Subsequently, the active duocarmycin is released and binds to DNA in the minor groove, followed by alkylation of the DNA and killing of the tumor cells. In vitro and in vivo experiments were performed to (directly) compare various pharmacodynamic and pharmacokinetic properties of SYD985 with those of the most progressed (marketing-approved) HER2-targeting ADC, i.e. ado-trastuzumab emtansine (T-DM1). T-DM1 is currently indicated for second line treatment of breast cancer patients overexpressing HER2 tumor tissue. In in vitro experiments, SYD985 shows potencies similar to T-DM1 in cell lines expressing HER2 at high levels (IHC HER2 3+), whereas SYD985 is significantly more potent compared to T-DM1 in cell lines expressing low HER2 levels (IHC HER2 2+ or 1+). In line with these results, SYD985 has superior efficacy compared to T-DM1 in xenograft models in which patient-derived breast cancer tumor tissue with low HER2 levels (IHC HER2 2+ or 1+/FISH-) have been used. Pharmacokinetic experiments (in vitro and in vivo) have revealed that whereas in mice SYD985 has limited stability, in cynomolgus monkey SYD985 is very stable. Excellent stability in vitro is also observed in human plasma. Moreover, after i.v. administration of SYD985 in the cynomolgus monkey the amount of free toxin (DUBA) detected in the monkey plasma is many-fold lower than levels reported for the toxin (DM1) released from T-DM1. Resuming, the preclinical data of SYD985 support clinical studies to investigate whether SYD985 has benefit in cancer patients with moderate or even low HER2 levels of the tumor tissue. Citation Format: Gijs Verheijden, Patrick Beusker, Ruud Ubink, Miranda van der Lee, Patrick Groothuis, Peter Goedings, David Egging, Marco Timmers, Wim Dokter. Preclinical data of SYD985 support the clinical investigation of this novel anti-HER2 antibody-drug conjugate in breast cancer patients with low levels of HER2 expression [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-14.