Abstract 1339: Pre-clinical development of IAMA-004, a tri-specific antibody targeting innate immune receptors and tumor targets

Abstract Immune check-point inhibitor (ICI) such as anti-PD1 or anti-PDL1 antibody, which enhances the adaptive immunity via re-energizing exhausted T cells, has become the foundational therapy for many cancers. However, due to variety of other immunosuppressive tumor microenvironments, it is efficacious only in 15-30% of the patients. It is well known both the innate immunity and the adaptive immunity are required for full control of cancer growth. Thus, therapeutics harnessing the innate immunity will be complementary to ICI and improve the cancer response rate when used in combination. Currently therapeutics harnessing the innate immunity mainly involve bispecific antibodies with one arm targeting tumor antigen and one arm connecting to innate effector cells such as NK cells or macrophages, represented by CD30-CD16a bispecific and Her2-CD47 bispecific respectively. Considering that cancer patient’s immune status are heterogenous, varying from T cell exhaustion, macrophage disfunction (M2 bias), Treg cell presence to NK cell deficiencies, it would be advantageous to combine several innate immunity enhancers into one therapeutic molecule. Here we describe a long-acting tri-specific antibody termed IAMA-004 that targets Her2 as the primary target and CD47 and CD16a as effector cell engagers. CD47 is also a co-target on some tumor cells (CD47-Her2 double positive tumors). We have characterized this molecule both in vitro and in vivo. The in vitro experiments tested the molecule’s ability to kill Her2 high, Her2 low and Her2 negative tumor cell lines including BT-474, SK-OV-3, NCI-N87, OE19, HCC1954, MDA-MB-231, MDA-MB-468, in human PBMC ADCC assays with DS-8201 and Trastuzmab as the comparator molecules. In all of these ADCC experiments, IAMA-004 showed superior tumor cell killing activities to those mediated by DS-8201 or Trastuzmab. When combined with IAMA-005 (a Fc-IL2-IFN-α fusion cytokine), the tumor cell killing activities were dramatically increased. In addition, IAMA-004 was also tested in patient-derived Ex-Vivo fluids (one malignant pleural effusion and one malignant asities) and demonstrated tumor cell killing efficacies; and the killing activity could be attributed to the specific arms of the molecule. These results suggest that it is feasible to combine more than one innate engager in one molecule to carry out specific functions in the heterogeneous immune status for the treatment of advanced cancer patients. Citation Format: Liming Liu, Zhen Han, Yang Fan, Qi Pan. Pre-clinical development of IAMA-004, a tri-specific antibody targeting innate immune receptors and tumor targets abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1339.