A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues. Experimental Design: The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3 þ T-cells. Results: Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3. Conclusions: This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.

Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

“…ScFv as a building block has been utilized in design of anti-DLL3 chimeric antigen receptor T cells, creating an investigational anti-Notch cancer cell therapeutic [ AMG 119,(105,106)]. Similarly, anti-DLL3 has been used to direct CD3 expressing cytotoxic T cells to DLL3-expressing small cell lung cancer as a half-life extended bispecific T cell engager (HLE BiTE; AMG 757) that results in antitumor activity (107). The structure of AMG 757 consists of a bispecific ScFv fused in tandem to one arm of an IgG1 LALA Fc for half-life extension (107,108).…”

“…Similarly, anti-DLL3 has been used to direct CD3 expressing cytotoxic T cells to DLL3-expressing small cell lung cancer as a half-life extended bispecific T cell engager (HLE BiTE; AMG 757) that results in antitumor activity (107). The structure of AMG 757 consists of a bispecific ScFv fused in tandem to one arm of an IgG1 LALA Fc for half-life extension (107,108). As such, a range of different antibody scaffolds with Notch targeting properties have reached human studies, resulting in a body of knowledge that may guide the design of future Notch targeting modalities.…”

Mechanisms of small cell lung cancer metastasis

“…DLL3 may play a role in the migration of SCLC cells (Furuta et al , 2019; Huang et al , 2019). DLL3 is an emerging target in SCLC (Morgensztern et al , 2019; Hipp et al , 2020) and it will be interesting in the near future to understand whether targeting this molecule can help block the formation of new metastases or slow the growth of established ones.…”

Novel immune engagers and cellular therapies for metastatic castration-resistant prostate cancer: do we take a BiTe or ride BiKEs, TriKEs, and CARs?

“…A second DLL-3 targetging BiTE, BI 764532, is under development by Boehringer Inhgelheim and consists of an anti-CD3 scFv and an anti-DLL3 scFV linked by an engineered Fc region. This also demonstrated target specificity, T-cell redirection and a half-life of 10 days( 54 ). A Phase 1 study ( NCT04429087 ) is currently enrolling patients with neuroendocrine tumors including prostate to evaluate the maximum-tolerated dose.…”