plozalizumab plevistinag (TAK-500) / Takeda - LARVOL DELTA

Short-term and long-term sting activation elicit divergent cellular responses in distinct hematopoietic populations in chronic myelomonocytic leukemia (ASH 2025) - "Dazostinag or TAK-500 depleted total and CCR2+ MNCs from CMML pts but not from HDsAccordingly, STING activation with dazostinag or TAK-500 induced a dose-dependent depletion ofmonocytic cell lines (MOLM13, THP1) through IRF3 phosphorylation and caspase 3 cleavage. In contrast to short-term STING activation, long-term TAK-500exposure was not associated with CCR2+ cell depletion, changes in LSK or progenitor populations ortransformation in KDM6B/Tet2 mice. scRNA-seq of MNCs revealed decreased expression of inflammatorygenes on monocyte and progenitor populations compared to short-term exposure which suggests cell-adaptive responses to overcome inflammatory and cell death programs associated with acute STINGactivation.Together, these data highlight the complex effects of STING activation dynamics in distinct hematopoieticpopulations and their role in CMML pathophysiology."

Clinical • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • CASP3 • CCR2 • CD14 • CD34 • GLI2 • IRF7 • KDM6B • PTPRC • STING • TET2

Sting-Mediated Interferon Signaling Exerts Potent Antileukemic Effects in High-Risk Myeloid and Monocytic Malignancies (ASH 2023) - "Evaluation of the efficacy of TAK-500 and dazostingag in patient-derived xenograft models of primary CMML samples is planned. Taken together, our data suggests that CCR2-directed STING activation might have therapeutic potential in HR-MyMo neoplasms by depleting CCR2+ cells and impairing clonal HSPC repopulation potential."

Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CASP3 • CCR2 • CD34 • GLI2 • IL15 • KDM6B • STING • TET2

Identification of a Novel Linker Enabling the Bioconjugation of a Cyclic Dinucleotide for the STING Antibody-Drug Conjugate TAK-500. (PubMed, Bioconjug Chem) - "The stochastic cysteine conjugation of the dazostinag containing these linkers provided ADC TAK-500 and its mouse surrogate mTAK-500 with DAR = 4. In syngeneic tumor-bearing mouse models, mTAK-500 showed target specific antitumor activity as well as the induction of immune-stimulating cytokines."

Journal • Oncology • CCR2 • CTSB • STING

A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=61 | Terminated | Sponsor: Takeda | Recruiting ➔ Terminated | Trial primary completion date: Aug 2026 ➔ Jan 2025 | N=313 ➔ 61 | Trial completion date: Aug 2026 ➔ Jan 2025; Clinical Futility of TAK 500 met. No further development with this compound

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Kidney Cancer • Liver Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody Drug Conjugate TAK-500. (PubMed, Cancer Immunol Res) - "Spatially resolved analysis of CCR2 and immune cell markers in the TME of >1,000 primary human tumors showed the CCR2 protein was predominantly expressed in intratumoral myeloid cells. Collectively, these data highlight the clinical potential of delivering a STING agonist to CCR2+ cells."

Journal • Oncology • Solid Tumor • CCR2 • STING

Preclinical impact of pretreatment with CRS mitigation agents on pharmacodynamic response to TAK-500, a systemically delivered CCR2-targeted STING agonist iADC (AACR 2024) - "Premedication of TAK-500 and mTAK-500 with dexamethasone or anti-IL-6R antibodies does not substantially impact STING-mediated innate immune activation, mobilization of adaptive immune responses or anti-tumor efficacy, despite altered cytokine profiles compared to (m)TAK-500 without premedication. Clinically, these premedication strategies have been effective in mitigating immunotherapy-associated CRS with T cell therapeutics, and here resulted in maintained anti-tumor activity when used in combination with TAK-500, suggesting a viable potential strategy for mitigation of STING-induced immunotoxicities in patients."

PK/PD data • Preclinical • Oncology • CCR2 • CD8 • IL10 • STING

Immunomodulatory and anti-tumor effect of a CCR2-targeted STING agonist iADC in human lung cancer (AACR 2024) - "Our results reveal prominent myeloid CCR2 expression in a subset of human NSCLCs with distinct clinicopathologic/molecular characteristics. Using a novel lung cancer explant ex vivo system, we demonstrate a CCR2-dependent immunomodulatory and anti-tumor effect of TAK-500 iADC."

Immunomodulating • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CASP3 • CCR2 • CD20 • CD4 • CD68 • CD8 • GZMB • ITGAM • KRAS • PD-L1 • TFRC

A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=313 | Recruiting | Sponsor: Takeda | Phase classification: P1a/1b ➔ P1/2 | N=118 ➔ 313 | Trial completion date: Mar 2025 ➔ Aug 2026 | Trial primary completion date: Mar 2025 ➔ Aug 2026

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Kidney Cancer • Liver Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

TAK-500 as a single agent and in combination with pembrolizumab in patients (pts) with advanced solid tumors: Rationale and design of a phase I/II study (ESMO 2023) - P1a/1b | "Background TAK-500 is a novel immune-cell-directed antibody drug conjugate comprising the STING agonist TAK-676 conjugated to a human IgG1 anti-C-C chemokine receptor 2 (CCR2) antibody. A single-stage statistical design will be utilized for 3rd-line NS NSCLC and RCC. As of May 2023, 6 sites in the United States are recruiting; the global phase 2 is planned to start in 2024."

Clinical • Combination therapy • Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Gastrointestinal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • CCR2

Targeting STING to CCR2+ Cells via an Immune Cell Directed Antibody Drug Conjugate (iADC) (ADC-USA 2023) - "Narrating an overview of the murine surrogate iADC, mTAK-500, which was designed to selectively deliver the a STING agonist to CCR2+ cells; Discussing the of nonclinical data and mechanistic insight that have motivated design and clinical testing of TAK-500, a CCR2-targeted STING ISAC comprising the clinical STING agonist TAK-676 and a high affinity antibody targeting human CCR2"

Immune cell • CCR2 • STING

Targeting STING to CCR2+ Cells via an Immune Stimulating Antibody Conjugate (PEGS 2023) - "STING signaling in intratumor myeloid cells can enhance interferon (IFN) production, boost local adaptive anti-tumor immunity, and could synergize with other anti-cancer therapies. We discuss nonclinical data for a novel iADC, TAK-500, which selectively activates STING in CCR2-expressing cells to enable systemic delivery, favor intratumor accumulation of the active compound, and achieve anti-tumor immunity."

Immune Modulation • Oncology • Solid Tumor • CCR2 • STING

TAK-500 is a clinical stage immune-cell directed antibody drug conjugate (iADC) inducing STING activation in CCR2-expressing intratumor myeloid cells and favorable immunomodulation (AACR 2023) - P1a/1b | "The iADC TAK-500 and mTAK-500 induces CCR2-dependent immune cell activation and anti-tumor effect. CCR2 is highly expressed in intratumor myeloid cells from NSCLC. High CCR2 is associated with enhanced local adaptive immune responses and specific clinical/molecular tumor subsets."

Clinical • Immune cell • Immunomodulating • IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCR2 • CD68 • CD8 • EGFR • ITGAM • KRAS • MSI • PD-L1 • STING

Preclinical activity of C-C chemokine receptor 2 (CCR2)-targeted immune stimulating antibody conjugate (ISAC), motivating clinical testing of TAK-500 (SITC 2022) - P1a/1b | "Single agent α-PD-1 treatment also resulted in a 12.5% CR rate, however, when combined, mTAK-500 and α-PD-1 treatment achieved enhanced anti-tumor response with a 37.5% CR rate. Conclusions Nonclinical antitumor activity and mechanistic insight have motivated design and clinical testing of TAK-500, a CCR2-targeted STING ISAC comprising the clinical stage STING agonist TAK-676 and a high-affinity antibody targeting human CCR2, as a single agent and in combination with pembrolizumab in adults with select locally advanced or metastatic solid tumors ( NCT05070247 )."

IO biomarker • Preclinical • Oncology • Solid Tumor • CCR2 • CD8 • STING

CCR2-targeted STING ISAC TAK-500 shows promising results as cancer immunotherapeutic (Bioworld) - "Activation of the cGAS-STING pathway activates the immune system through the production of type I interferons. There is knowledge that myeloid cell populations are among the most sensitive to STING agonism. Investigators at Takeda Pharmaceutical Co. Ltd. presented results on TAK-500, an immune stimulant antibody-drug conjugate (ISAC) composed of an antibody linked to a STING agonist for delivery to CCR2+ cells."

Preclinical • Oncology

Phase 1a/1b study design of the novel STING agonist, immune-stimulating antibody-conjugate (ISAC) TAK-500, with or without pembrolizumab in patients with advanced solid tumors. (ASCO 2022) - P1, P1a/1b | "TAK-500 is a novel ISAC comprising a STING agonist (based on TAK-676, which is currently in phase 1 clinical trials [NCT04420884, NCT04879849]), an IgG1 anti-cysteine-cysteine chemokine receptor 2 (CCR2) antibody, and a self-immolating maleimide-containing protease-cleavable peptide linker. In the dose expansion phase, only the combination of TAK-500 + pembrolizumab will be evaluated. Primary objectives of this study are safety and tolerability; secondary objectives include determination of the PAD range, the recommended phase 2 dose, pharmacokinetics, pharmacodynamics, and antitumor activity of TAK-500 as a single agent and in combination with pembrolizumab."

Clinical • P1 data • Breast Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Inflammation • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD8 • STING

First-in-human study of TAK-500, a novel STING agonist immune stimulating antibody conjugate (ISAC), alone and in combination with pembrolizumab in patients with select advanced solid tumors (AACR 2022) - P1, P1a/1b | "TAK-500 is an ISAC that consists of three parts: a STING agonist payload based on TAK-676 (currently under phase 1 clinical evaluation [NCT04420884, NCT04879849]), the IgG1 anti-CCR2 antibody (previously evaluated in early phase studies), and a self-immolating maleimide-containing protease-cleavable peptide linker. A subsequent dose expansion phase will evaluate TAK-500 in combination with pembrolizumab. Planned enrollment for both escalation and expansion cohorts is ~106 patients."

Clinical • Combination therapy • P1 data • Breast Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD8 • STING

Preclinical activity of C-C chemokine receptor 2 (CCR2)-targeted immune stimulating antibody conjugate (ISAC), motivating clinical testing of TAK-500 (AACR-NCI-EORTC 2022) - No abstract available

Preclinical • Oncology • CCR2

A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1a/1b | N=106 | Recruiting | Sponsor: Takeda | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • STING