A LAIR-1 targeting antibody drug conjugate for hematologic cancers.

Abstract

e15022 Background: LAIR-1 is a receptor expressed on the surface of hematopoietic cells subsets that negatively regulates immune activity. It is also highly and broadly expressed on the surface of many leukemia and lymphoma cells. Differential signaling of LAIR-1 in leukemia can confer a survival advantage to these cancer cells. These features make LAIR-1 an attractive therapeutic target in hematologic cancers. Previous studies have shown that a LAIR-1 targeting agonist antibody induced leukemic cell death. Here, we sought to determine if targeting LAIR-1 with an antibody drug conjugate (ADC) would be safe and efficacious in hematologic cancers expressing LAIR-1. Methods: LAIR-1 expression was assessed in leukemias and lymphomas by IHC and RNA. In vitro assays were run to screen for internalization of a LAIR-1 monoclonal antibody (mAb) in tumor cell lines and PBMCs. The LAIR-1 mAb was conjugated with various cytotoxic payloads to evaluate in vitro killing of leukemic cells, as well as for safety in mice engineered to express the human LAIR-1 extracellular region under the endogenous LAIR-1 promoter, and retaining murine transmembrane and cytoplasmic regions. The LAIR-1 mAb conjugated with various payloads was tested in human patient cell-line derived (CDX) tumor models of leukemia and lymphoma for anti-tumor activity. Results: LAIR-1 was broadly and highly expressed in AML. Some T cell lymphomas also expressed high levels of LAIR-1. LAIR-1 was rapidly internalized in vitro in tumor cells but not human PBMCs. An in vitro cytotoxicity assay testing a LAIR-1 ADC mAb killed tumor cells dependent on the level of LAIR-1 expression. Safety was tested in human LAIR-1 knock-in (KI) mice since the LAIR-1 mAb does not cross-react with murine LAIR-1. Human LAIR-1 KI blood and spleen immune cell populations and frequencies did not change following treatment with LAIR-1 ADC, and various payloads conjugated to LAIR-1 showed no toxicity of any ADCs based on weight loss. Various LAIR-1 ADCs were tested for activity in both leukemia and lymphoma in vivo CDX tumor models. Potent regression and control of tumor was observed with LAIR-1 ADC in comparison to naked LAIR-1 mAb and control. Conclusions: LAIR-1 ADCs appear safe in human LAIR-1 KI mice. LAIR-1 ADC was highly effective in eradicating and controlling both leukemia and lymphoma tumors that expressed LAIR-1. Together, this study supports the development of a LAIR-1 ADC for the treatment of LAIR-1 expressing hematological cancers.