5O - GBR1302-BEAT ® bispecific antibody targeting CD3 and HER2 demonstrates a higher anti-tumor potential than current HER2-targeting therapies
|Date||04 November 2016|
|Event||ESMO Symposium on Immuno-Oncology 2016|
|Session||Proffered paper session|
|Citation||Annals of Oncology (2016) 27 (suppl_8): viii1-viii2. 10.1093/annonc/mdw525|
Current HER2-targeting therapies (such as Herceptin or TDM-1) have demonstrated efficacy only in cancers significantly overexpressing HER2 (cancers characterized as HER2 3+ according to the IHC HercepTest®) and are also limited by several possible resistance mechanisms. Bridging T lymphocytes to HER2 tumor cells has the potential to trigger a more efficient elimination of tumor cells. Using the Glenmark BEAT® platform, we have produced a bispecific antibody, GBR 1302, targeting human CD3ε and HER2 and designed to effectively recruit cytotoxic T lymphocytes against HER2 positive cancer cells. These studies aimed at comparing the potency of GBR 1302 and the current HER-2 targeting therapies.
Short term (48 hours) in vitro killing assays, against different breast or gastric tumor cell lines characterized as HER2 3+ or 2+ by IHC HercepTest and using resting human PBMCs from healthy donors as effector cells. Metabolic or colony forming readouts were performed to quantify tumor cell death. In vivo tumor xenograft models, either subcutaneous or disseminated (intravenous injection of the cells). The tumor cells were grafted with human PBMCs to bring effector cells. The treatments were started the day of the tumor+PBMC graft.
Killing experiments comparing the potency of GBR 1302 to current HER2-targeting therapies such as trastuzumab or T-DM1 highlighted a more efficient, rapid and complete cytotoxic potential for GBR 1302 against a variety of tumor cells. In particular, killing assays on breast or gastric tumor cell lines characterized as HER2 3+ or 2+ by IHC HercepTest, followed by a clonogenic readout or an absolute count of viable target cells, revealed a significantly more complete killing by GBR 1302 as compared to T-DM1. Tumor xenograft models confirmed these data, by showing that T-DM1 could only slow subcutaneous tumor growth, or delay the time of sacrifice of mice in a metastatic model, while GBR 1302 was able to abrogate almost completely tumor development.
These observations highlight that GBR 1302, consistent with its mechanism of action, is able to trigger a rapid and very potent mobilization of T lymphocyte cytotoxic functions against cancer cells. These features warrant for GBR 1302 a potential to elicit in patients a more complete response in a shorter period compared to current HER2 targeting treatments which are essentially cytostatic drugs, thereby limiting the probability of the emergence and Darwinian selection of resistant cells.
Clinical trial identification
Legal entity responsible for the study
Glenmark Pharmaceuticals S.A
Glenmark Pharmaceuticals S.A
J. Back: Employee of Glenmark Pharmaceuticals S.A