Abstract 2980: HX009, a first-in-class PD1xCD47 BsAb, demonstrated anti-AML activity in PDX models
Authors: An Xiaoyu , Liu Jinping , Ke Hang , Xiong Lingxin , Tu Xiaolong , Zhang Lei , Zhang Faming , Li Henry 
Published: April 2023

Abstract
Acute myeloid leukemia (AML) is an aggressive leukemia of myeloid lineage with different subtypes (global annual mortality ~150,000). The first-line treatment is usually induction chemotherapies, followed by further chemo-/radiation therapies or stem cell transplant, etc. Immune checkpoint inhibitor (ICIs), e.g. PD1 blocker, although a great success for treating many solid tumors, has yet to show convincing activity in AML. CD47, a “don’t eat me” receptor frequently found on the surface of tumor cells, including hematological malignances such as AML, prevents phagocytosis by interacting to its ligand, SIRPα, on the surface of macrophages. CD47 is also now shown as a key immune checkpoint for both innate and adoptive immunity (Liu et al., 2018). CD47 targeting, actively being tested for MSD and AML in clinics, encounters challenges for the reported toxicities (e.g. anemia/thrombocytopenia) as well as inadequate efficacy (Feng et al., 2019). Majority of investigational CD47 targeting agents in the clinics are combination therapies with other modality in order to increase the likelihood of success. To this end, it is prudent to develop agents with dual targeting agents, particularly for both the innate and adoptive immune checkpoints. We describe a novel specially designed/constructed bi-specific antibody (BsAb), HX009, targeting CD47 and PD1 for the treatment of cancers. We tested HX009 in several preclinical AML-PDXs (patient-derived xenograft models) via systemic engraftment: AM8096 (CD47lo, H-score of 55 by IHC), AM7577 (CD47hi, H-score of 237)(An et al., 2017) and AM5512 (CD47hi, H-score of 198). All three PDXs responded to 10mg/kg twice weekly dose of HX009 (IP) as measured either by leukemic burden in peripheral blood at different timepoints, and in both spleen and bone marrow at the termination, or by survival. Since there is no T-cell function in xenograft models, all anti-leukemic activities observed should be attributed to the CD47 blockade, not PD1 blockade. AM7577 model responded significantly better than AM8096, likely due to the significantly higher expression of CD47 and also better than Ara-C standard of care (SOC) treatment at 3mg/kg. In contrast, AM8096 responded even less to HX009 than Ara-C. In contrast, in the subcutaneous transplanted AML cell line-derived model, MV4-11, there is little anti-tumor activity observed, although there is significant expression of CD47 on the tumor cells. In conclusion, our data seems to suggest that HX009 could be a candidate immunotherapy for CD47hi AML, with CD47 expression being a positive predictive biomarker, warranting further evaluation.
Citation Format: Xiaoyu An, Jinping Liu, Hang Ke, Lingxin Xiong, Xiaolong Tu, Lei Zhang, Faming Zhang, Henry Li. HX009, a first-in-class PD1xCD47 BsAb, demonstrated anti-AML activity in PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2980.