780 ALTA-002, a SIRPα-directed TLR9 agonist antibody conjugate activates myeloid cells and promotes anti-tumor immunity

Background

Novel therapies engaging both innate and adaptive immune responses may engender durable anti-tumor immunity. Activation of toll-like receptor 9 (TLR9) by unmethylated CpG oligonucleotides promotes innate inflammatory responses and induces adaptive immunity. Immune cells expressing TLR9 encompass B cells and myeloid cells (including dendritic cells and plasmacytoid dendritic cells). Recently, several TLR9 agonists have demonstrated clinical benefit in patients with melanoma when administered intra-tumorally.¹ Specifically designed for systemic administration, we developed a novel Toll-like Receptor Agonist Antibody Conjugate (TRAAC) molecule comprised of a differentiated TLR-9 agonist (T-CpG) conjugated to an antibody against SIRPα (ALTA-002). Signal regulatory protein α (SIRPα) is a myeloid inhibitory receptor that suppresses immune activation following binding of its ligand CD47. Blockade of CD47-SIRPα myeloid checkpoint pathway has been shown to promote myeloid-mediated anti-tumor functions leading to the induction of adaptive immunity.² Additionally, SIRPα is highly expressed in various tumor types including renal cell carcinoma and melanoma.³ Here we present preclinical data demonstrating that ALTA-002 delivers T-CpG to SIRPα expressing myeloid cells, triggering TLR9 signaling, cell activation and immune modulation resulting in robust anti-tumor efficacy.

Methods

In vitro activity of ALTA-002 was evaluated using human PBMCs co-cultured in the presence of SIRPα positive and negative tumor cells. Anti-tumor efficacy of mouse ALTA-002 surrogate was evaluated in multiple syngeneic tumor models with varying immunogenicity profiles.

Results

In vitro co-culture of human PBMC and SIRPα positive or negative tumor cells with ALTA-002 stimulates myeloid cells, leading to increased IRF7 induction, expression of co-stimulatory molecules, and cytokine secretion. In vitro treatment with ALTA-002 led to enhanced phagocytic engulfment by human monocyte-derived macrophages across multiple SIRPα positive and negative tumor cell lines. Following systemic delivery of a mouse ALTA-002 surrogate, durable anti-tumor activity was observed in both SIRPα positive and negative expressing tumors. ALTA-002 treated mice with eradicated tumors suppressed tumor growth upon tumor re-challenge, indicating tumor-specific immune memory.

Conclusions

These results demonstrate the unique properties of systemically administered ALTA-002, which integrates TLR9 activation and blockade of CD47-SIRPα interaction on myeloid cells to engender both innate and adaptive anti-tumor immune responses. These data support the development of ALTA-002 as an anti-cancer therapeutic for a variety of tumor malignancies.

References

Hamid O, Ismail R, Puzanov I. Intratumoral Immunotherapy-Update 2019. Oncologist 2020;25(3):e423-e4382. Kuo T, Chen A, Harrabi O. Targeting the myeloid checkpoint receptor SIRPα potentiates innate and adaptive immune responses to promote anti-tumor activity. J Hematol Oncol 2020;13:160–1783. Yanagita T, Murata Y, Tanaka D. Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy. JCI Insight 2017;2(1):e89140.

Ethics Approval

In vivo studies were approved by the Institutional Animal Care and Use Committee of Tallac Therapeutics.