The Anti-Tumor Activity of Igm-8444, an Agonistic Death Receptor 5 (DR5) IgM Antibody, Is Sensitized in Combination with Chemotherapy and Bcl-2 Inhibitors in NHL and AML

Background:

Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF) receptor superfamily that multimerizes when bound to its ligand, TNF-related apoptosis inducing ligand (TRAIL), to activate the extrinsic apoptotic pathway. DR5 is broadly expressed on solid and hematologic cancers and has been targeted with both recombinant TRAIL and agonistic antibodies in the clinic. However, these therapeutics have been unsuccessful due to lack of efficacy or hepatotoxicity. We have developed IGM-8444, a pentameric IgM with 10 binding sites specific for DR5, that multimerizes DR5 to selectively and potently induce tumor cell apoptosis while maintaining tolerability. We have previously presented the in vitro and in vivo efficacy of IGM-8444 in solid tumor models, demonstrating low picomolar potency across multiple tumor cell lines, strong tumor regressions in cell line and patient derived xenograft mouse tumor models, and dose-dependent increases in apoptotic biomarkers. Here, we evaluate the activity of IGM-8444 in hematologic malignancies in combination with chemotherapy or targeted agents including Bcl-2 inhibitors targeting the intrinsic apoptotic pathway.

Methods:

Human hematologic cancer cell lines and primary human hepatocytes were evaluated in vitro for dose-dependent IGM-8444-induced cytotoxicity. Cell lines were further evaluated using IGM-8444 in combination with chemotherapy or targeted agents including Bcl-2 inhibitor ABT-199. In vivo efficacy was evaluated using IGM-8444 in combination with ABT-199 in cell line-derived xenograft mouse tumor models.

Results:

In a previous cancer cell line screen profiling single agent IGM-8444 cytotoxicity across 190 solid and hematologic cell lines, 25 (13%) were classified as highly responsive and 75 (39%) as moderately responsive to IGM-8444 induced cell death. Here the in vitro activity of IGM-8444 was evaluated across a subset of 32 NHL and AML cell lines. 5/21 (24%) of NHL cell lines and 5/11 (45%) of AML cell lines tested were classified as highly responsive or moderately responsive to IGM-8444-induced cytotoxicity. The DOHH-2 and JEKO1 NHL cell lines were amongst the most sensitive, with growth-normalized EC50 values as low as 0.03 ng/mL (0.03 pM) for JEKO1. Combinations with chemotherapy including cytarabine and doxorubicin or targeted agents such as Bcl-2 inhibitor ABT-199 resulted in synergistic in vitro cytotoxicity in multiple cell lines, as determined by Bliss synergy scores. IGM-8444 demonstrated minimal to no in vitro cytotoxicity to primary human hepatocytes at doses several log-fold higher than efficacious doses, and this favorable in vitro safety profile was maintained in combination with chemotherapeutic agents and ABT-199. Combination of IGM-8444 with ABT-199 also resulted in synergistic in vivo efficacy. In a DOHH-2 NHL model, IGM-8444 and ABT-199 showed modest tumor growth inhibition as single agents. However the combined treatment regimen led to tumor regressions during the first 2 weeks of treatment, with 3 of 10 animals showing a partial response and 2 of 10 animals achieving a complete response. The combined treatment also extended median overall survival compared to the control group, which was a significant improvement compared to either agent alone. Collectively, these results provide a strong rationale for simultaneously targeting the extrinsic and intrinsic apoptotic pathways to achieve enhanced efficacy.

Conclusions:

These data support the clinical development of IGM-8444 in hematological malignancies as a single agent, in combination with standard of care chemotherapy, and in combination with targeted agents that impact the intrinsic signaling pathway such as Bcl-2 inhibitor ABT-199. Initiation of a Phase I clinical study evaluating the safety of IGM-8444 is anticipated in 2020.