SYD985 ([vic-] Trastuzumab Duocarmazine) Drug Description

SYD985 ([vic-]trastuzumab duocarmazine) an antibody-drug conjugate or ADC being developed by Synthon Biopharmaceuticals (Nijmegen, The Netherlands), consists of the recombinant humanized anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab linked, via a cleavable linker, to the duocarmycin prodrug, seco-duocarmycin-hydroxybenzamide-azaindole orseco-DUBA, which has potential antineoplastic activity.

Following administration of trastuzumab vc-seco-DUBA, the trastuzumab moiety binds to HER2 on the tumor cell surface.  This, in turn, triggers the endocytosis of this agent. The linker is then cleaved inside the tumor cell by proteases at the dipeptide valine-citrulline (vc), and releases the active moiety, duocarmycin.

Duocarmycin binds to the minor groove of DNA, alkylates adenine at the N3 position, and induces cell death. In addition, trastuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells that overexpress HER2.

The average drug-to-antibody ratio of SYD985 is DAR2 and DAR4.

In vivo antitumor studies in breast cancer patient-derived xenograft (PDX) models have shown that SYD985 is very active in HER2 3+, 2+, and 1+ models, whereas, in a head-to-head study with ado-trastuzumab emtansine (also know as T-DM1; Kadcyla®; Genentech/Roche), another trastuzumab-based antibody-drug conjugate, ado-trastuzumab emtansine only showed significant antitumor activity in HER2 3+ breast cancer PDX models. [1]

The properties of SYD985 may enable expansion of the target population to patients who have low HER2-expressing breast cancer, a patient population with still unmet high medical need

HER2 overexpression is associated with a poor prognosis.