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DRUG:

BTN2A1/3A1-Fc-CD19scFv

i
Other names: BTN2A1/3A1-Fc-CD19scFv, CD19 targeting GADLEN, CD19 targeting Gamma Delta T cell engager
Associations
Trials
Company:
Shattuck
Drug class:
CD19 inhibitor, γδ TCR modulator
Related drugs:
Associations
Trials
2years
Cutting Edge: Bispecific γδ T Cell Engager Containing Heterodimeric BTN2A1 and BTN3A1 Promotes Targeted Activation of Vγ9Vδ2 T Cells in the Presence of Costimulation by CD28 or NKG2D. (PubMed, J Immunol)
Using a tumor cell-free assay, we demonstrated that a BTN2A1/3A1 heterodimeric fusion protein activated human Vγ9Vδ2 T cells, but only in the presence of costimulatory signal via CD28 or NK group 2 member D. Nonetheless, addition of a bispecific γδ T cell engager BTN2A1/3A1-Fc-CD19scFv alone enhanced granzyme B-mediated killing of human CD19 lymphoma cells when cocultured with Vγ9Vδ2 T cells, suggesting expression of costimulatory ligand(s) on tumor cells is sufficient to satisfy the "signal 2" requirement. These results highlight the parallels of signal 1 and signal 2 requirements in αβ and γδ T cell activation and demonstrate the utility of heterodimeric BTNs to promote targeted activation of γδ T cells.
Journal • IO biomarker
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CD19 (CD19 Molecule) • GZMB (Granzyme B) • BTN2A1 (Butyrophilin Subfamily 2 Member A1) • BTN3A1 (Butyrophilin Subfamily 3 Member A1) • NKG2D (killer cell lectin like receptor K1)
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BTN2A1/3A1-Fc-CD19scFv
over2years
Bispecific gamma delta T cell engagers containing butyrophilin 2A1/3A1 heterodimeric fusion protein efficiently activate Vg9Vd2 T cells and promote tumor cell killing (AACR 2022)
In addition, the CD33-targeted GADLEN alone was able to specifically kill acute myeloid leukemia cells expressing CD33 and costimulatory ligands (e.g., CD80 and CD86) in a mechanism similar to the CD19-targeted GADLEN construct. These results highlight the ability of GADLENs in promoting targeted killing of tumor cells by providing the “active” heterodimeric BTN2A1 and BTN3A1 that is critical to enhance cytotoxic killing by Vγ9Vδ2 T cells. Furthermore, this study provides mechanistic insights into BTN-mediated activation of Vγ9Vδ2 T cells and offers proof of concept for using antigen-targeted butyrophilin heterodimeric fusion proteins for the treatment of cancer.
IO biomarker
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CD19 (CD19 Molecule) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • CD33 (CD33 Molecule) • CD28 (CD28 Molecule) • BTN2A1 (Butyrophilin Subfamily 2 Member A1) • MICA (MHC Class I Polypeptide-Related Sequence A) • BTN3A1 (Butyrophilin Subfamily 3 Member A1) • CD86 (CD86 Molecule) • MICB (MHC Class I Polypeptide-Related Sequence B) • NKG2D (killer cell lectin like receptor K1)
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CD19 expression
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BTN2A1/3A1-Fc-CD19scFv