Reference Detail

Ref Type

Abstract

PMID

Authors

Kristan Meetze; Naveen K. Mehta; Martin Pfluegler; Bochong Li; Patrick A. Baeuerle; Jennifer S. Michaelson; Gundram Jung; Helmut Salih

Title

CLN-049 is a bispecific T cell engaging IgG-like antibody targeting FLT3 on AML cells

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	82	12_Supplement	June 15, 2022

URL

https://aacrjournals.org/cancerres/article/82/12_Supplement/2078/700859/Abstract-2078-CLN-049-is-a-bispecific-T-cell

Abstract Text

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with few options for curative treatment. In lymphoid malignancies, the introduction of chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) has achieved remarkable success. However, such immunotherapeutic strategies are not yet established for AML, likely due to a dearth of appropriate targets. The fms like tyrosine kinase 3 (FLT3)/CD135 surface receptor is expressed on AML cells in the large majority of AML patients and constitutes a highly selective target antigen for immunotherapy, as expression on healthy tissues is limited to low levels on dendritic cells, monocytes and hematopoietic progenitor cells. We report here on the development of CLN-049, a bispecific humanized antibody that binds to FLT3 on leukemic cells and the CD3 epsilon subunit of the T cell receptor complex on T cells. CLN-049 recognizes the membrane proximal domain of FLT3 and has a silenced Fc gamma 1 domain, with anti-CD3 single chain variable fragments (scFv) fused to the C-termini of the heavy chains. While FLT3 kinase inhibitors are limited to treatment of patients with specific intracellular FLT3 mutations, CLN-049 recognizes the extracellular domain of FLT3 and would therefore be more broadly applicable in AML therapy. CLN-049 showed low-nanomolar binding to both FLT3-expressing and CD3-expressing cells. The antibody induced target-dependent activation of CD4+ and CD8+ T cells as well as corresponding cytokine production by T cells only when co-cultured with FLT3+ AML cells. Human AML cell lines expressing a broad range of surface levels of FLT3 were efficiently lysed upon treatment with sub-nanomolar concentrations of CLN-049 when co-cultured with heterologous PBMCs, regardless of the expression level or mutational status of FLT3. Intriguingly, FLT3-expressing hematopoietic progenitor cells and dendritic cells were not found to be sensitive to CLN-049 killing. The in vitro lysis of leukemic cells by CLN-049 was not affected by supraphysiological levels of soluble FLT3 or FLT3 ligand. In mouse xenograft studies, CLN-049 was highly active against the MOLM-13 human AML model. In these studies, CLN-049 demonstrated significant dose-dependent activity as measured by survival as well as reduction of AML cells in the blood. In summary, CLN-049 is a promising FLT3-targeted T cell engaging antibody construct expected to have robust anti-tumor activity in the clinic against AML. CLN-049 is currently in a phase 1 clinical trial for the treatment of patients with relapsed/refractory AML.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CLN-049	CLN-049	1	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CLN-049		CLN049\|CLN 049	CD3 Antibody 92 FLT3 Antibody 5	CLN-049 is a bispecific antibody that targets FLT3 and CD3, potentially inducing activation of CD4- and CD8-positive T cells and inhibiting tumor growth (Cancer Res 2022;82(12_Suppl):Abstract nr 2078).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 positive	acute myeloid leukemia	predicted - sensitive	CLN-049	Preclinical - Cell line xenograft	Actionable	In a preclinical study, CLN-049 decreased growth and increased survival in a cell line xenograft model of FLT3-positive acute myeloid leukemia (Cancer Res 2022;82(12_Suppl):Abstract nr 2078).	detail...