Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models

Abstract

Alemtuzumab is a recombinant humanized IgG1 monoclonal antibody directed against CD52, an antigen expressed on the surface of normal and malignant B and T lymphocytes. Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined. To address this issue, the anti-tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models. The density of CD52 target antigen on the surface of tumor cells appeared to correlate with the anti-tumor activity of alemtuzumab. Deglycosylation of alemtuzumab resulted in a loss of cytotoxicity in vitro and was found to abolish anti-tumor activity in vivo. Individual inactivation of effector mechanisms in tumor-bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells. Increasing the number of circulating neutrophils by treatment with G-CSF enhanced the anti-tumor activity of the antibody, thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab.

Synergistic Innate and Adaptive Immune Response to Combination Immunotherapy with Anti-Tumor Antigen Antibodies and Extended Serum Half-Life IL-2

“…Tumor-associated neutrophils are often considered as pro-tumor “N2” polarized neutrophils (Fridlender and Albelda, 2012) and the immunosuppressive granulocytic-subtype of myeloid derived suppressor cells also possess a similar phenotype (Gabrilovich et al, 2012). However, there are examples where neutrophils are required for antibody therapeutic effects in xenograft tumor control studies (Eisenbeis et al, 2003; Schneider-Merck et al, 2010; Siders et al, 2010). In fact, it seems intuitive to utilize the underappreciated neutrophil to mount an anti-tumor response given that they are the most abundant of circulating leukocytes, and in other forms of immune challenge, neutrophils are the first responders, inducing massive cell-killing.…”

Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica

“…ADCC is the principal mechanism in cancer therapy involving the targeting of tumor cells by monoclonal antibodies (29). ADCC involves binding of the antibody Fc region to receptors on effector cells, such as CD16 (FcγRIII) on NK cells, and CD64 (FcγRI), CD32 (FcγRII), and CD16 on neutrophils and eosinophils (30)(31)(32). CDC is thought to be the major pathogenic mechanism in NMO, based in part on the perivascular deposition of activated complement in human NMO lesions, and the generation of NMO-like pathology in mice administered NMO-IgG and complement.…”

Synergistic cytotoxicity of ex vivo expanded natural killer cells in combination with monoclonal antibody drugs against cancer cells

“…We experienced a patient with metastatic breast cancer refractory to a cytotoxic agent, and trastuzumab was improved when combined with infusion of a large number of ex vivo expanded NK cells [55]. Besides rituxumab [17,[44][45][46][47], many other therapeutic mAbs are being developed such as trastuzumab [48][49][50], cetuximab [52], and alemtuzumab [56] and their routine use for a range of hematological and solid tumors may provide many potential combinations with expanded NK cell therapy to be broadly applicable to a wide range of malignancies.…”