Strategy for specific delivery of antisense oligonucleotides to T cells

PROJECT SUMMARY Antisense oligonucleotides (ASOs) are promising drugs given their potential to modify expression of disease- related genes, including those previously considered ‘undruggable’. Despite their clinical potential, their success has been limited to hepatic, muscular and neurodegenerative conditions due to limitations with delivering ASOs

to tissues other than liver, muscle and the central nervous system (CNS), which are tissues with either rich distribution of ASOs or specific delivery methods. Unfortunately, applications to immunological conditions or conditions that could benefit from immuno-modulation (e.g., cancer, vaccines) have been limited due to the lack

of effective tools to deliver ASOs to immune cells in vivo, in particular to T cells. Accordingly, delivery tools that could enhance the efficiency and specificity of ASO delivery to T cells remain a critical unmet need. To address this critical need, ABS is developing a modular delivery platform to target ASOs specifically to T cells

utilizing conjugated mono-specific monoclonal antibodies (mmAbs) against T cell-specific cell surface receptors. mmAbs are highly specific antibodies that have been screened against the human proteome and selected for their exclusive binding to the target protein. Such selectivity screen is not usually employed in the development

of monoclonal antibodies, resulting in antibodies that bind to other proteins besides their intended target, thereby enhancing potentially toxic effects due to off-target binding. Accordingly, the mmAbs proposed here have the potential to enhance delivery of ASOs to T cells while reducing potential toxic effects of the antibody conjugate.

ABS’ T cell-specific delivery platform takes advantage of the T cell-predominant expression of the Programmed Cell Death Protein 1 (PDCD1, PD1, CD279) and Interleukin 2 Receptor Subunit Beta (IL2RB, CD122). Besides their T cell-predominant expression, their biological roles in T cells make them attractive candidates. PDCD1 is

highly expressed in tumor-infiltrating T cells and mediates suppression of these tumor-reactive T cells, thereby hindering their efficacy to kill cancer cells. Accordingly, -PDCD1 antibodies could have a dual role in enhancing tumor reactivity by directing immuno-modulatory ASOs to these critical cells, while also relieving the PDCD1-

mediated suppression of tumor-reactive T cells. IL2RB promotes receptor-mediated endocytosis in T cells, and here we leverage this function to target and drive internalization of the conjugated ASO specifically in T cells. The goal of this Phase I proposal is to test the efficiency and specificity of -PDCD1 and -IL2RB mmAbs to

deliver the conjugated ASOs to T cells ex vivo and in mice. Successful completion of this goal will validate the utility of ABS’ T cell-specific delivery platform to deliver ASOs to T cells in vivo. This modular delivery platform will have broad impact on human health given its wide applicability for treatment of cancers, immunodeficiencies,

autoimmune and infectious diseases, and applications in vaccine development. In the ensuing Phase II proposal, we will create a mono-specific nanobody of the optimal mmAb to further improve its therapeutic index, and test its efficacy and safety to deliver ASOs to T cells in mice and nonhuman primates.