Abstract 5546: A murine reactive version of TAK-573 (anti-CD38 attenuated IFNα fusion protein) shows immunomodulatory and antitumor activity, alone and in combination with standard-of-care agents, in IFNa-insensitive, immunocompetent murine multiple myeloma tumor models
Authors: Hara Tomoya , Wong Christina , Yu Jie , Collins Sabrina , Wang Haiqing , Sugimoto Hiroshi , Zhang Hong , Bjorck Pia , Curley Michael D. 
Published: September 2020

Abstract
Background: Despite improvements in outcome for patients treated with triplet and quadruplet based regimens, multiple myeloma is still a relapsing and ultimately fatal disease. We previously reported that targeting an investigational attenuated form of IFNα, or Attenukine™, to multiple myeloma (MM) tumor cells via direct fusion to an anti-CD38 antibody (TAK-573) has direct anti-proliferative activity on MM cancer cells in vitro and induces robust and durable responses in MM xenograft tumor models, alone and in combination with standard-of-care (SOC) agents. Here, we further elucidate the broad immunomodulatory impact and antitumor activity of a murine reactive version of TAK-573, anti-mouse CD38-attenuated murine IFNα (mCD38-mATT), alone and in combination with SOC agents in immunocompetent murine tumor models of MM.
Methods: Murine CD38 receptor expression and direct sensitivity to murine IFNα (mIFNα) of 2 murine MM cell lines were characterized. Murine MM cell line-derived tumor models were established in immunocompetent mice and antitumor activity of mCD38-mATT treatment was evaluated alone and in combination with approved SOC agents for MM. Pharmacodynamic changes in the tumor immune microenvironment post-treatment were determined using multicolor flow cytometry.
Results: Both MM murine tumor cell lines were insensitive to direct mIFNα treatment, indicating a reliance on immune-mediated antitumor activity when tested in vivo. Immunoprofiling analyses post-administration with single-agent mCD38-mATT indicated increased prevalence and activation of NK cells in peripheral blood and increased intratumoral CD8+ T: Treg and CD8+ T: CD4+ T cell ratios, compared to anti-mCD38 antibody or murine IFNα alone. Follow-on experiments evaluating single-agent mCD38-mATT indicated modest activity on tumor growth in vivo. Combination administration of mCD38-mATT with SOC agents had increased anti-tumor activity compared to either single-agent administration alone.
Conclusion: Administration of mCD38-mATT induced broad immunomodulation and antitumor responses, alone and in combination with SOC agents in immunocompetent mouse models, highlighting the impact of this agent on CD38+ cells, both tumor and immune. These results support further investigation of combination therapies in the ongoing clinical evaluation of TAK-573 in a Phase 1 trial in patients with relapsed refractory MM.
Citation Format: Tomoya Hara, Christina Wong, Jie Yu, Sabrina Collins, Haiqing Wang, Hiroshi Sugimoto, Hong Zhang, Pia Bjorck, Michael D. Curley. A murine reactive version of TAK-573 (anti-CD38 attenuated IFNα fusion protein) shows immunomodulatory and antitumor activity, alone and in combination with standard-of-care agents, in IFNa-insensitive, immunocompetent murine multiple myeloma tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5546.