Pipeline – TAK-500

Overview^1-2

TAK-500 is a first-in-class STING agonist immunostimulatory antibody drug conjugate (iADC) that delivers dazostinag to CCR2+ myeloid cells in the tumor microenvironment

Mechanism of Action^1,3-4

- By targeting the STING pathway and CCR2 expressing myeloid cells, TAK-500 may offer enhanced potency via improved PK and selective delivery. TAK-500 has three possible mechanisms of action: activation of IFN response, reprogramming of suppressive intratumoral CCR2+ myeloid cells, and blockade of suppressive tumor-associated macrophage recruitment

- Activation of STING leads to the production of proinflammatory cytokines that activate dendritic cells, macrophages, and natural killer cells, and subsequently mobilize adaptive immune cells against tumor cells

- Combining TAK-500 with radiation and/or checkpoint inhibitors led to enhanced antitumor activity in preclinical studies

- Dying tumor cells release tumor antigens and tumor-derived cGAMP, which continue to activate the STING pathway

TAK-500 is an investigational therapy. The mechanism of action is based on preclinical data. Clinical efficacy and safety have not been determined.

CD8, cluster of differentiation 8; CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif chemokine receptor 2; CcGAMP, cyclic guanosine monophosphate-adenosine monophosphate; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; IFN, interferon; IP-10, interferon gamma-induced protein 10; IRF-3, interferon regulatory factor 3; NK, natural killer; PD-L1, programmed cell death-ligand 1; PD-1, programmed cell death protein 1; STING, stimulator of interferon genes; TNF, tumor necrosis factor.

Clinical Trials

Study Name

An Open-label, Dose Escalation and Expansion, Phase 1a/1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-500, a Novel Stimulator of Interferon Genes Agonist, as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Select Locally Advanced or Metastatic Solid Tumors

References

1. Diamond JR, Henry JT, Falchook GS, et al. Phase 1a/1b study design of the novel STING agonist, immune-stimulating antibodyconjugate (ISAC) TAK-500, with or without pembrolizumab in patients with advanced solid tumors. Journal of Clinical Oncology. 2022;40(16). Web Link

2. Appleman V, Matsuda A, Ganno M, et al. PRECLINICAL ACTIVITY OF C-C CHEMOKINE RECEPTOR 2 (CCR2)-TARGETED IMMUNE STIMULATING ANTIBODY CONJUGATE (ISAC), MOTIVATING CLINICAL TESTING OF TAK-500. Journal for ImmunoTherapy of Cancer. 2022;10:A1194. Web Link

3. Cooper B, Chmura SJ, Luke JJ, et al. Phase 1 study of TAK-676 + pembrolizumab following radiation therapy in patients with advanced nonsmall-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN). Cancer Res. 2022;82(12). Web Link

4. Yum S, Li M, Chen ZJ. Old dogs, new trick: classic cancer therapies activate cGAS. Cell Res. 2020;30(8):639-648. doi:10.1038/s41422-020-0346-1