Fc-Effector Function Activity Of The Cxcr4 Igg1 Antibody Pf-06747143: A Novel Clinical Candidate For The Treatment Of Hematologic Malignancies

Abstract The chemokine receptor CXCR4 triggers signaling pathways that control cell migration to tissues where its ligand, CXCL12, is highly expressed, including the bone marrow (BM). In hematologic cancers, CXCR4 expression is associated with poor prognosis. CXCR4-driven homing of malignant cells to the BM protective niche is a key mechanism of chemotherapy resistance. PF-06747143 is a novel humanized IgG1 therapeutic antibody that binds to CXCR4 and inhibits CXCL12-driven pathways. Human IgG1 antibodies can induce strong cytotoxicity mediated by the antibody Fc-region, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-driven cytotoxicity, while human IgG4 antibodies show minimal or no Fc-driven cytotoxicity. Here we generated an IgG4 version of PF-06747143 (m15-IgG4), which has similar binding to CXCR4 as the IgG1 antibody. We then characterized the role of Fc-driven cytotoxic function, comparing both antibodies in efficacy and safety studies. In an ADCC assay, PF-06747143 showed strong cytotoxicity of non-Hodgkin’s lymphoma (NHL) and acute myeloid leukemia (AML), while m15-IgG4 had no significant cytotoxicity. In a NHL mouse tumor model, the IgG1 CXCR4 antibody resulted in superior tumor growth inhibition, with 50% of mice exhibiting complete tumor regressions, compared to the m15-IgG4 antibody, which had limited activity, with no tumor regressions (p<0.01). The two antibodies had comparable exposure, suggesting that the difference in efficacy is due to the IgG1 antibody Fc-driven cytotoxic function. Furthermore, CXCR4 inhibition was previously shown to induce leukocyte mobilization from the BM; however, prolonged cell mobilization may lead to safety related issues, including hyperleukocytosis. In a study in non-human primates, we show that the IgG1 CXCR4 antibody elicited short leukocyte mobilization, lasting 16-24 hrs, while m15-IgG4 induced prolonged cell mobilization, lasting > 4 days. Since both antibodies had comparable exposures, the different mobilization duration is likely due to the ability of the IgG1 CXCR4 antibody to reduce the number of mobilized cells via Fc-driven cytotoxic function. Finally, CXCR4 has been shown to play a key role in chemotherapy resistance. In a chemo-resistant PDX AML mouse model, in which the standard of care agents daunorubicin and cytarabine had limited activity, resulting in 30% of tumor cells remaining in the BM post-treatment, we show that combination of PF-06747143 with these chemo agents led to synergistic activity, with tumor burden reduced to 0.3% tumor cells in the BM. In conclusion, PF-06747143 attributes offer potential efficacy- and safety-related advantages over other CXCR4 antagonists currently in development, which do not have Fc-driven cytotoxic activity. PF-06747143 is now being evaluated in a Phase 1 clinical trial in relapsed and refractory AML (NCTID 02954653). Citation Format: Flavia Pernasetti, Shu-Hui Liu, Gu Yin, Bernadette Pascual, Zhengming Yan, Max Hallin, Rolla Yafawi, Cathy Zhang, Connie Fang, Wenlian Wang, Justine Lam, Mary E. Spilker, Eileen Blasi, Brett Simmons, Nanni Huser, Wei-Hsien Ho, Kevin Lindquist, Thomas-Toan Tran, Jyothirmayee Kudaravalli, Jing-Tyan Ma, Gretchen Jimenez, Ishita Barman, Colleen Brown, Sherman-Michael Chin, Maria Costa, David Shelton, Tod Smeal, Valeria R. Fantin. Fc-effector function activity of the CXCR4 IgG1 antibody PF-06747143: a novel clinical candidate for the treatment of hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2649. doi:10.1158/1538-7445.AM2017-2649