Article Text

Download PDFPDF

1121 TAC-003, a TLR9 agonist antibody conjugate for targeted immunotherapy of Nectin-4 expressing tumors
  1. Amy Chen,
  2. Min Li,
  3. Emma RB Sangalang,
  4. Danielle Fontaine,
  5. Tiffany Chou,
  6. Mingrui An,
  7. Maja Bonacorsi,
  8. Bora Han,
  9. Hong I Wan,
  10. Maria Jose Costa and
  11. Pavel Strop
  1. Tallac Therapeutics Inc., Burlingame, CA, USA


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.


  1. Hamid O, Ismail R, Puzanov I. Intratumoral Immunotherapy-Update 2019. Oncologist, 2020 Mar;25(3):e423-e438.

  2. 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.

  3. 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

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.