RT Journal Article
SR Electronic
T1 1121 TAC-003, a TLR9 agonist antibody conjugate for targeted immunotherapy of Nectin-4 expressing tumors
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP A1234
OP A1234
DO 10.1136/jitc-2023-SITC2023.1121
VO 11
IS Suppl 1
A1 Chen, Amy
A1 Li, Min
A1 Sangalang, Emma RB
A1 Fontaine, Danielle
A1 Chou, Tiffany
A1 An, Mingrui
A1 Bonacorsi, Maja
A1 Han, Bora
A1 Wan, Hong I
A1 Costa, Maria Jose
A1 Strop, Pavel
YR 2023
UL http://jitc.bmj.com/content/11/Suppl_1/A1234.abstract
AB Background Activation of Toll-Like Receptor 9 (TLR9) by unmethylated CpG oligodeoxynucleotides (CpG ODNs) promotes innate and adaptive immune responses. Tumor microenvironment (TME) modulation using TLR9 agonists has emerged as a promising strategy in cancer immunotherapy with evidence of clinical activity in melanoma when CpG ODNs are injected intratumorally.1 However, most solid tumors are not amenable to intratumoral therapeutic intervention. A systemically delivered, tumor targeted, TLR9 agonist has potential to ignite anti-tumor immunity in multiple cancer types. Nectin-4 is a cell adhesion molecule with limited expression in normal tissues but over-expressed in many solid tumor types and is a clinically validated cancer-associated antigen.2 We developed a Toll-like Receptor Agonist Antibody Conjugate (TRAAC) comprised of a novel Nectin-4 antibody conjugated to a potent CpG ODN, for systemic administration and activation of TLR9 in the immune microenvironment of Nectin-4 expressing cancers. Previously, we showed that Nectin-4 TRAAC induces immune activation leading to durable anti-tumor efficacy, including in checkpoint inhibitor refractory tumors.3 Here, we expand on the mode of action of the Nectin-4 TRAAC clinical candidate, TAC-003, and show that systemic administration of a TAC-003 murine surrogate results in tumor honing, pro-inflammatory responses within the TME and superior efficacy, as compared to a Nectin-4 antibody drug conjugate (ADC). Importantly, TAC-003 showed a favorable safety profile.Methods TAC-003 in vitro activity was evaluated by flow cytometry using human peripheral blood-derived immune cells co-cultured with cancer cells bearing various levels of Nectin-4 expression. Biodistribution and efficacy studies were performed in mouse syngeneic tumor models using a TAC-003 murine surrogate. The safety profile of TAC-003 was assessed in cynomolgus monkeys.Results In vitro, TAC-003 induces activation of innate and adaptive immune cells, resulting in increased cytokine levels and up-regulation of co-stimulatory molecules. TAC-003 enhances cancer cell phagocytosis, in a manner that correlates with Nectin-4 expression levels. In vivo, the TAC-003 murine surrogate binds to Nectin-4 expressing cancer cells, leading to its preferential accumulation in tumor as compared to normal tissues with low/no Nectin-4 expression. Accordingly, mice treated with TAC-003 murine surrogate show increased levels of pro-inflammatory cytokines in tumor as compared to spleen. This differentiated mechanism of action results in superior anti-tumor efficacy when compared to a Nectin-4 ADC. TAC-003 shows a favorable safety profile in toxicity studies performed in cynomolgus monkeys.Conclusions The preclinical data presented here provides compelling rationale for further development of TAC-003 as an immunotherapy for Nectin-4-expressing solid tumors.ReferencesHamid O, Ismail R, Puzanov I. Intratumoral Immunotherapy-Update 2019. Oncologist, 2020 Mar;25(3):e423-e438.Chatterjee S, Sinha S, Kundu CN. Nectin cell adhesion molecule-4 (NECTIN-4): a potential target for cancer therapy. Eur J Pharmacol. 2021 Nov 15;911:174516.Chen A, Li M, Bonacorsi M, et al. 1162 A nectin-4 targeted TLR9 agonist antibody conjugate induces robust immune cell activation and anti-tumor responses. Journal for ImmunoTherapy of Cancer. 2022;10