Abstract
The prevailing view is that therapeutic antibodies deplete cells through opsonization and subsequent phagocytosis, complement-dependent lysis or antibody-dependent cellular-cytotoxicity. We used high resolution in vivo imaging to identify a new antibody-dependent cell death pathway where Kupffer cells ripped large fragments off crawling antibody-coated iNKT cells. This antibody-dependent fragmentation process resulted in lethality and depletion of crawling iNKT cells in the liver sinusoids and lung capillaries. iNKT cell depletion was Fcy-receptor dependent and required iNKT cell crawling. Blood, spleen or joint iNKT cells that did not crawl were not depleted. The antibody required high glycosylation for sufficiently strong binding of the iNKT cells to the Fc Receptors on Kupffer cells. Using an acetaminophen overdose model, this approach functionally depleted hepatic iNKT cells and affected the severity of liver injury. This study reveals a new mechanism of antibody-dependent killing in vivo and raises implications for the design of new antibodies for cancer and auto-reactive immune cells.
Highlights
Development of antibodies to eliminate target cells has become a hugely successful experimental and therapeutic approach
While the anti-CD20 antibody is regularly employed as a hematological cancer therapeutic and represents a breakthrough in the treatment of B cell malignancies[12,13,14], these anti-CD20-specific antibodies, as well as CD52 specific alemtuzumab, Her2/neu-specific trastuzumab, EGRF-specific cetiuximab and anti-GD-2 antibodies are all under investigation in clinical trials to target depletion of both cancer and immune cells[10, 15,16,17]
Results invariant Natural Killer T (iNKT) cells in liver are depleted by an anti-CXCR3 antibody (CXCR3-173)
Summary
Development of antibodies to eliminate target cells has become a hugely successful experimental and therapeutic approach. In ADCC-mediated cell death, the binding of cytotoxic cells (for example, NK cells) to antibody-opsonized tumor cells result in the release of vesicular contents such as perforin and granzymes which lyse and kill the tumor cells[3]. The use of therapeutic antibodies to target tumor cells has implicated trogocytosis, the process of ripping off or nibbling and internalizing small bits of the target cell membrane, instead of phagocytosis of whole cells[7]. The CC chemokine receptor 4 (CCR4)-targeting glyco-engineered antibody, mogamulizumab, has enhanced ADCC with no known explanation, but has recently been approved in Japan for use in patients with relapsed and refractory CCR4-positive adult T cell leukemia/lymphoma[35]. Since most interrogations are done in cell culture systems devoid of blood flow and other important in vivo micro-environmental factors, the mechanisms of action of these antibodies remain equivocal
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