Monoclonal antibody‐mediated killing of tumour cells by neutrophils

Abstract

Neutrophils represent the most abundant population of circulating cytotoxic effector cells. Moreover, their number can be easily increased by treatment with granulocyte‐colony stimulating factor or granulocyte macrophage‐colony stimulating factor, without the need for ex vivo expansion. Because neutrophils express Fc receptors, they have the potential to act as effector cells during monoclonal antibody therapy of cancer. Additionally, as neutrophils play a role in the regulation of adaptive immune responses, exploiting neutrophils in mAb therapy may result in long‐term antitumour immunity. There is limited evidence that neutrophils play a prominent role in current immunoglobulin G‐based immunotherapy. However, as IgA induces neutrophil recruitment, novel therapeutic strategies that aim to target the IgA Fc receptor FcαRI may fully unleash the potential of enlisting neutrophils as cytotoxic effector cells in antibody therapy of cancer.

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

“…Particularly, IgA antibodies, which specifically bind the IgA Fcα receptor I (FcαRI or CD89) present on cells of the myeloid lineage, including neutrophils ( 237 ), are currently considered as a promising approach in immunotherapy against cancer because of their superior ability to induce neutrophil-mediated ADCC. This was reported for a number of tumor-associated antigens such as Ep-CAM for colon carcinoma, HER2/neu for breast carcinoma, EGFR for epithelial, colorectal and renal cell carcinoma, HLA class II, CD20 and CD30 for B-cell lymphoma, and carcinoembryonic antigen as shown in in vitro studies ( 127 , 128 , 238 – 242 ). The induction of such stronger cytotoxic responses upon an IgA engagement of human neutrophils could be explained by the higher avidity of FcαRI which binds bivalently to IgA, and hence recruit more ITAMs to initiate a more robust signaling to activate effector functions ( 242 ).…”

“…These mAbs can initiate direct tumor cell killing, through the F(ab’) 2 domains of the immunoglobulin (Ig) interfering with the intrinsic function of the target cell ( 121 , 122 ), or upon binding of the Fc part to the C1q component of the complement system inducing complement-dependent cytotoxicity (CDC) ( 123 ). Besides the direct mechanisms, the Fc region of the mAb can also bind to activating Fc receptors on innate immune cells which will in turn elicit indirect-mediated killing via antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/P) of the opsonized cells ( 124 – 128 ).…”

“…Noteworthy, immature neutrophils that were mobilized from the bone marrow after G-CSF treatment triggered a more efficient ex vivo tumor cell lysis in the presence of an IgA antibody compared to IgG ( 244 , 245 ). Based on this we speculate that the use of IgA antibodies could unleash the cytotoxic potential of G-CSF mobilized immature neutrophils in antibody therapy of cancer that otherwise would be immunosuppressive, or even trigger re-polarization of PMN-MDSCs, due to FcαRI constitutive expression ( 128 ). In an in vivo setting, however, the use of IgA tumor-targeting antibodies is restricted due to the lack of an FcαRI homolog in mice.…”

IgA: Structure, Function, and Developability

“…Another alternative to target FcαRI consists in the use of bispecific antibodies (BsAb). By virtue of combining two distinct antigen binding capabilities, BsAb are able to target tumours and recruit immune cells, such as neutrophils, leading to tumour cell killing by antibody-dependent cellular cytotoxicity mechanisms [181]. The use of a BsAb against both HER2 and FcαRI (namely anti-HER2 × FcαRI) efficiently eliminated breast carcinoma cells by neutrophil accumulation, unlike the equivalent FcγRI-directed BsAb (anti-HER2 × FcγRI) [182].…”

IgA subclasses have different effector functions associated with distinct glycosylation profiles

“…Evidence exists that serum IgA contributes to autoimmune diseases, such as inflammatory bowel disease 6,7 , autoimmune skin blistering diseases 8,9 , or rheumatoid arthritis (RA) [10][11][12] as well as to transplant rejection 13 . In addition, IgA has gained interest as a therapeutic antibody against cancer cells, as it activates neutrophilmediated antibody-dependent cellular cytotoxicity better than IgG 14,15 .…”