Depletion of Blood Antigen-Presenting Cells by IMMU-114: Therapeutic Potential Against Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation. Since antigen-presenting cells (APCs) play a critical role in initiating GVHD, selective depletion of host APCs before or during preparative conditioning may yield an improved approach for prevention of GVHD compared to the prevailing therapies, which often compromise the pre-existing T-cell immunity against opportunistic pathogens. IMMU-114 (Immunomedics, Inc.) is an anti-human HLA-DR humanized IgG4 monoclonal antibody (mAb) with a point mutation (Ser241Pro) in the hinge region of the γ4 sequence to avoid the formation of half molecules, and has direct cytotoxicity against a variety of HLA-DR-expressing hematological malignancies. In this study, we investigated the effects of IMMU-114 on the subsets of human blood APCs, and evaluated its effects on the proliferation of alloreactive T cells and preexisting anti-viral memory T-cell immunity in allogeneic mixed leukocyte cultures.

We assessed the effects of IMMU-114 on T cells and all subsets of APCs in human peripheral blood mononuclear cells, including dendritic cells (DCs), B cells, and monocytes. In order to evaluate the therapeutic potential of IMMU-114 against GVHD, we tested the effect of IMMU-114 on the proliferation of alloreactive T cells in allogeneic mixed leukocyte cultures; In order to evaluate the direct effect of IMMU-114 on T cells, we tested the effect of IMMU-114 on the proliferation of already proliferated T cells, and to evaluate the impact of IMMU-114 on preexisting T-cell immunity, we measured the effect of IMMU-114 on HLA-A2-restricted, CMV-specific CD8+ memory T cells by pentamer assay.

IMMU-114 depleted almost all subsets of APCs, including dendritic cells (DCs), B cells, and monocytes from human peripheral blood mononuclear cells without affecting the survival of T cells. Specifically, the myeloid DCs type 1 (mDC1) were depleted by 59.2% (P = .0022), myeloid DCs type 2 (mDC2) by 84.8% (P<.0001), plasmacytoid DCs (pDCs) by 52.2% (P = .1927), B cells by 86.2% (P<.0001), and monocytes by 74.7% (P = .01139). In addition, IMMU-114 suppressed the proliferation of alloreactive T cells in mixed leukocyte cultures, yet had no effect on the proliferation of already proliferated T cells. These results suggest that IMMU-114 has therapeutic potential against GVHD, which may be through the depletion of APCs rather than a direct effect on T cells. Importantly, the result demonstrated that CMV-specific, CD8+ memory T cells were preserved in IMMU-114-treated allogeneic mixed leukocyte cultures, suggesting that IMMU-114 may not affect the preexisting anti-viral T-cell immunity, which is essential for immunological control of opportunistic infections following stem cell transplantation.

These results indicate that IMMU-114 may be a promising novel agent for prevention and treatment of GVHD through the depletion of APCs. It also supports the investigation of IMMU-114 as a novel component of conditioning regimens for preventing GVHD without alteration of preexisting anti-viral immunity, which would have a distinct advantage over currently available agents for GVHD prevention. (Supported in part by NIH grant PO1-CA103985.)

Chang:Immunomedics, Inc.: Employment, Equity Ownership, Patents & Royalties. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.