Dataset Information

Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.

ABSTRACT:

Objectives

Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab.

Methods

Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed.

Results

Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9.

Conclusion

Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.

SUBMITTER: Schwartz S

PROVIDER: S-EPMC9525012 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.

Schwartz Stephanie S Patel Nidhi N Longmire Tyler T Jayaraman Pushpa P Jiang Xiaomo X Lu Hongbo H Baker Lisa L Velez Janelle J Ramesh Radha R Wavreille Anne-Sophie AS Verneret Melanie M Fan Hong H Hu Tiancen T Xu Fangmin F Taraszka John J Pelletier Marc M Miyashiro Joy J Rinne Mikael M Dranoff Glenn G Sabatos-Peyton Catherine C Cremasco Viviana V

Immunotherapy advances 20220810 1

<h4>Objectives</h4>Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab.<h4>Methods</h4>Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also as ...[more]

PMID: 36196369

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Project description:BackgroundSuccessful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial experiences with CD19 CAR T cell immunotherapy for patients with B-cell malignancies highlighted the critical impact of intracellular costimulatory domain selection (CD28 vs 4-1BB (CD137)) on CAR T cell expansion and in vivo persistence that may impact clinical outcomes. However, the impact of costimulatory domains on the efficacy of myeloid antigen-directed CAR T cell immunotherapy remains unknown.MethodsIn this preclinical study, we developed six CAR constructs targeting CD33, a highly expressed and validated AML target, comprised of one of three single-chain variable fragments with CD3ζ and either CD28 or 4-1BB costimulatory domains. We systematically compared the preclinical in vitro and in vivo efficacy of T cells lentivirally transduced with CD33 CAR constructs (CD33CARTs) against human AML.ResultsWe observed potent in vitro cytokine production and cytotoxicity of CD33CARTs incubated with human CD33+ AML cell lines, as well as robust in vivo antileukemia activity in cell line and childhood AML patient-derived xenograft (PDX) models. Gemtuzumab-based CD33CARTs were unexpectedly toxic in vivo in animal models despite observed in vitro anti-leukemia activity. CD28-based CD33CARTs consistently induced more robust inhibition of leukemia proliferation in AML cell line and PDX models than did 4-1BB-based CD33CARTs. A 'best-in-class' lintuzumab-CD28/CD3ζ CAR construct was thus selected for clinical translation.ConclusionsCD33 is a critical antigen for potential immunotherapeutic targeting in patients with AML. Based on this rigorous preclinical evaluation, our validated clinical grade lintuzumab-CD28/CD3ζ CD33CART immunotherapy is now under evaluation in a first-in-child/first-in-human phase 1 clinical trial for children and adolescents/young adults with relapsed/refractory AML.Trial registration numberclinicaltrials.gov; NCT03971799.

Dataset Information

Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.

Objectives

Methods

Results

Conclusion

Publications

Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.

Similar Datasets

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