Abstract 1721: TAC-001, a toll-like receptor 9 (TLR9) agonist antibody conjugate targeting B cells, promotes anti-tumor immunity and favorable safety profile following systemic administration in preclinical models
Authors: Kuo Tracy C. , Harrabi Ons , Chen Amy , Sangalang Emma R. , Doyle Laura , Fontaine Danielle , Li Min , Han Bora , Pons Jaume , Sim Janet , Wan Hong I. 
Published: July 2021

Novel therapies capable of engaging both innate and adaptive immune responses may engender durable anti-tumor immunity. Activation of toll-like receptor 9 (TLR9) by unmethylated oligonucleotides promotes innate inflammatory responses and the induction of adaptive immunity. Recently, several CpG-based TLR9 agonists have demonstrated clinical benefit in melanoma patients when administered intra-tumorally. Immune cells expressing TLR9 include B cells, plasmacytoid dendritic cells and myeloid cells. In B cells, TLR9 activation in human and mouse drives B cell proliferation and differentiation. Recent studies have described the presence and potential role of B cells in the response to checkpoint inhibitors in multiple solid tumor types. Specifically, enrichment of memory B cells, plasma cells and tertiary lymphoid organs have been observed in the tumors of responders to checkpoint inhibitors.

We developed a novel Toll-like Receptor Agonist Antibody Conjugate (TRAAC) platform to deliver a potent and differentiated TLR9 agonist (T-CpG) for targeted immune activation via systemic administration. TAC-001 is comprised of T-CpG conjugated to an anti-CD22 antibody, a receptor restricted to B cells. It is designed to systemically deliver T-CpG to B cells by binding CD22 receptor on B cells, leading to TLR9 signaling, B cell activation and a cascade of immune reactions. We show that the innate and adaptive immune responses triggered by TAC-001 leads to potent anti-tumor activity. In vitro stimulation of B cells with TAC-001 leads to increase expression of co-stimulatory molecules, cross-presentation leading to T cell proliferation and induction of immunoglobulin secretion. In mice, systemic delivery of a murine reactive anti-CD22-CpG conjugate shows durable single agent activity in PD-1 refractory and PD-1 resistant tumors. Mice with eradicated tumors acquire memory immune response upon tumor rechallenge. The cellular response in mice treated with TAC-001 exhibit B cell differentiation with significant decrease in IL-10+Bregs, along with increased in T cell effector function and modulation in suppressive myeloid cells within the tumor microenvironment. Systemic intravenous administration of TAC-001 in monkeys showed favorable tolerability, PK and PD profiles. These results demonstrate the unique properties of TAC-001 which integrates TLR9 activation and B cells to employ both innate and adaptive immune responses to promote anti-tumor activity. These data support the development of TAC-001 for a broad range of solid tumor malignancies.

Citation Format: Tracy C. Kuo, Ons Harrabi, Amy Chen, Emma R. Sangalang, Laura Doyle, Danielle Fontaine, Min Li, Bora Han, Jaume Pons, Janet Sim, Hong I. Wan. TAC-001, a toll-like receptor 9 (TLR9) agonist antibody conjugate targeting B cells, promotes anti-tumor immunity and favorable safety profile following systemic administration in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1721.