Evaluation of anti-CD83 monoclonal antibodies for the diagnosis and treatment of Hodgkin lymphoma and mantle cell lymphoma

Abstract

Lymphoma affects approximately 6400 Australians yearly and can develop in people of all ages. Monoclonal antibodies that target specific antigens have been shown effective in lymphomas but resistance occurs. Scientists have sought for novel therapeutical targets for lymphomas. CD83 is a member of the immunoglobulin superfamily. To date, the main utility of CD83 is to identify the activated dendritic cells. Our group described the CD83 expression by a malignant lymphoma cell line, KM-H2, more than 20 years ago. In this thesis, I examined the potential of CD83 as a therapeutic target for two subtypes of lymphoma, Hodgkin lymphoma (HL) and mantle cell lymphoma (MCL). I described CD83 was highly/moderately expressed by HL (82.9%) and MCL (61.1%) primary samples. I also reported that soluble CD83 (sCD83), an immune regulatory molecule, was detectable in HL patient plasma. Importantly, sCD83 secreted by Hodgkin and Reed-Sternberg (HRS) cells contributed to the immune inhibitory tumour microenvironment of HL. In vitro study showed that sCD83 inhibited T cell proliferation. An in-house human monoclonal antibody targeting lymphoma CD83+ cells, namely 3C12C, was effective in mediating antibody dependent cell cytotoxicity. Toxin conjugated form of this antibody eliminated CD83+ lymphoma cells in vitro and in vivo in a xenografted mouse model. To obtain insights into the effect and safety profiles of anti-CD83 antibody infusions, a dose-escalation trial of 3C12C infusion was performed in non-human primates, the baboons. In vivo studies showed that treatment of baboons with 3C12C did not alter liver and kidney function, and the cell count of white blood cells, although I did observe the transient regulatory T cells count increased and the DCs and B cells decreased in the peripheral blood. The level of changes appeared to be dose-dependent. These studies provide the foundation and safety profiles for CD83 as a potential therapeutic target for lymphoma. The human anti-CD83 antibody-drug conjugate is a novel approach for CD83 positive HL and MCL.