Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with a poor prognosis and high unmet medical need2. DLL3 is a therapeutic target that is selectively expressed in SCLC and other neuroendocrine tumors. Bispecific TCEs targeting DLL3 have entered the clinic and demonstrated encouraging anti-tumor activity in SCLC patients3,4; however, SCLC is frequently characterized by an immunosuppressive microenvironment and poor T cell infiltration, which may limit clinical activity of CD3 engagers5. DLL3 TriTCE Co-Stim is a TriTCE designed to optimally engage CD3 and CD28 to redirect and enhance cytotoxic T cell responses to DLL3-expressing tumor cells while maintaining a desired safety profile. This approach has the potential to improve outcomes for patients, especially those with poorly infiltrated tumors, by increasing the depth and durability of response.
Using Zymeworks’ TriTCE Co-stim platform in combination with our Azymetric™️ and EFECT™️ technologies, we generated a panel of DLL3 TriTCE Co-Stim antibody formats and evaluated multiple formats, geometries, and paratope affinities, which allowed for optimization of selectivity and activity to promote a widened therapeutic index with enhanced anti-tumor activity.
Key Results:
Induces greater in vitro cytotoxicity and improves T cell proliferation and survival compared to bispecific TCEs.
Displays no cross-linking of T cells and exhibits obligate cis T cell binding of CD28, requiring co-engagement of CD3.
Mediates improved in vivo tumor regression in an established SCLC humanized xenograft model relative to a clinical benchmark TCE.