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1162 A nectin-4 targeted TLR9 agonist antibody conjugate induces robust immune cell activation and anti-tumor responses
  1. Amy Chen,
  2. Min Li,
  3. Maja Bonacorsi,
  4. Emma Sangalang,
  5. Danielle Fontaine,
  6. Ons Harrabi,
  7. Mingrui An,
  8. Tiffany Chou,
  9. Laura Doyle,
  10. Janet Sim,
  11. Bora Han,
  12. Hong Wan,
  13. Tracy Kuo,
  14. Maria Jose Costa and
  15. Pavel Strop
  1. Tallac Therapeutics Inc, Burlingame, CA, USA


Background Novel therapies that engage 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 the induction of adaptive immunity. Several CpG-based TLR9 agonists have demonstrated clinical activity in melanoma by inducing a pro-inflammatory tumor microenvironment (TME), when administered intratumorally.1 However, intratumoral delivery has various development challenges that need to be addressed, including limited tumor indications, injection site variability and poor pharmacokinetics. A systemically delivered TLR9 agonist with favorable safety profile has potential to provide innate and adaptive anti-tumor immunity across multiple tumor types. We developed a Toll-like Receptor Agonist Antibody Conjugate (TRAAC) comprised of a CpG oligodeoxynucleotide conjugated to a novel Nectin-4-targeting antibody for systemic administration and TME delivery of a potent TLR9 agonist. Nectin-4 is a cancer associated antigen over-expressed in many solid tumor types with limited expression in normal tissues. Additionally, Nectin-4 over-expression correlates with poor prognosis.2 Activation of myeloid cells via TLR9 signaling within the TME may promote pro-inflammatory signals countering immunosuppressive pathways, thereby resulting in initiation and enhancement of anti-tumor responses.3 Here we present preclinical data demonstrating that Nectin-4 TRAAC triggers TLR9 signaling, induces myeloid and dendritic cell activation, phagocytosis, cytokine production and lymphocyte activation, resulting in potent anti-tumor efficacy.

Methods In vitro activity of Nectin-4 TRAAC was evaluated using human peripheral blood mononuclear cells (PBMCs) co-cultured in presence of Nectin-4 expressing cancer cells. The anti-tumor efficacy of Nectin-4 TRAAC as a monotherapy was evaluated using syngeneic models.

Results Nectin-4 TRAAC induced both innate and adaptive anti-tumor immune mechanisms in human PBMC co-cultured with Nectin-4-expressing cancer cell lines. Nectin-4 TRAAC potently activated myeloid cells, leading to enhanced phagocytosis, increased expression of co-stimulatory molecules, secretion of pro-inflammatory cytokines and B, T and NK cell activation. In both immunogenic and checkpoint inhibitor (CPI) refractory syngeneic tumor models, single agent Nectin-4 TRAAC treatment led to durable tumor regression and eradication across a range of Nectin-4 expression levels. Animals in which Nectin-4 TRAAC treatment led to tumor clearance were protected from tumor growth upon rechallenge, demonstrating that Nectin-4 TRAAC induces potent anti-tumor immunological memory.

Conclusions The preclinical data shown here provide a strong rationale for pursuing Nectin-4 TRAAC for the treatment of Nectin-4-expressing solid tumors, including those that are refractory to CPI therapy.


  1. Hamid O, Ismail R, Puzanov I. Intratumoral immunotherapy-update 2019. Oncologist 2020;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;911:174516.

  3. Liu M, O’Connor R, Trefely S. Graham K, Snyder NW, Beatty GL. Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated ‘don’t eat me signal. Nat Immunol 2019;20(3):265–275.

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