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.
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.
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