Friday, February 24, 2017

Drugs in Clinical Pipeline: MCLA-117 | CLEC12AxCD3 Bispecific Immunoglobulin G (IgG) | Bispecific Antibody I Treatment for Acute Myleoid Leukemia (AML)

MCLA-117 is a full length human CLEC12AxCD3 bispecific immunoglobulin G (IgG) that incorporates CH2 region amino acid substitutions to abrogate Fcγ receptor and C1q interactions while retaining its binding to FcRn. MCLA-117 binds to CD3, a cell-surface molecule present on all T cells, and CLEC12A, a cell surface molecule present on Acute Myleoid Leukemia (AML) cells and stem cells. MCLA-117 is designed to recruit and activate T-cells to kill CLEC12A-expressing AML tumor cells and stem cells, which may prevent recurrence of tumors. MCLA-117 redirects patient's cytotoxic T cells to induce AML tumor lysis.

Treatment for Acute Myleoid Leukemia
New Drug for Treatment for Acute Myleoid Leukemia

MCLA-117 is a human full length IgG1 bispecific antibody that uses an IGKV1-39/IGKJ1 common light chain (cLC) together with anti-CLEC12A-specific VH and an anti-CD3-specific VH. The Fc portion of MCLA-117 was engineered to selectively facilitate heavy chain heterodimerization and to abrogate Fcγ receptor and C1q-mediated effector function. The MCLA-117 affinity for CLEC12A is 60-fold greater than for CD3, 3 nM vs 177 nM respectively, which is predicted to facilitate the preferential opsonization of the AML blasts with MCLA-117.

What is CLEC12A?
CLEC12A is a myeloid differentiation antigen that is expressed on 90-95% of newly diagnosed and relapsed AML. Moreover, CLEC12A is selectively expressed on leukemic stem cells (LSCs) but not normal early hematopoietic progenitors, including hematopoietic stem cells (HSCs).

Dosages and Approvals:
MCLA-117 is being developed by Merus pharmaceuticals, and it is presently in Phase I/II stage [1, 2]. In preclinical studies, MCLA-117 has been shown to recruit and activate the immune system’s own T-cells to kill AML tumor cells and stem cells.

1. Van Loo, P. F.; et. al. Preclinical Evaluation of MCLA117, a CLEC12AxCD3 Bispecific Antibody Efficiently Targeting a Novel Leukemic Stem Cell Associated Antigen in AML. Blood 2015, 126, 325. (free article)
2. A Phase 1, Multinational Study of MCLA-117 in Acute Myelogenous Leukemia. NCT03038230
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