Oligomannose antigens as conserved immunological targets of Non-Hodgkin lymphomas

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PROJECT SUMMARY Non-Hodgkin lymphoma (NHL) is primarily of B-cell origin but is substantially heterogeneous, which makes developing a tumor-specific immunotherapy for it difficult. Recent advances in immune check-point inhibitor- directed and pan-B marker-targeted immunotherapies are alternative strategies to bypass the problem of tumor heterogenicity and have achieved promising therapeutic effects. However, targeting both tumor cells and normal cells remains an intrinsic disadvantage because such treatments may cause undesired and even lethal side effects. Thus, there is an unmet need for new targeting strategies to further advance immunotherapy for NHL. Our tumor glycomics team at SRI International studies immunologically important glycan markers that are potentially useful in diagnostic and/or therapeutic applications. Recently, we found high-mannose autoantigens were overexpressed in tissues of diffuse large B-cell lymphomas (DLBCLs), a major class of aggressive NHL. In addition, we found that several newly established Man9-specific mAbs recognize the cell-surface markers co- expressed by a murine B-lymphoma A20 and the Raji and Ramos human B-lymphoma cell lines (Preliminary Results). Thus, the BMan9 autoantigens are likely evolutionarily conserved and may serve as “pan” markers for B-lymphoma targeting; anti-BMan9 mAbs are, therefore, promising candidates for use in developing targeted immunotherapies to treat major NHL tumor subtypes. Our antibody engineering team at University of California, Los Angeles has developed multiple platforms of recombinant antibodies to improve therapeutic efficacy. Notably, these include humanized polymeric IgGs and immunocytokines. The polymeric IgG platform can be used to trap and eradicate circulating tumor cells and cancer stem cells (CTCs/CSCs) in vivo, and the immunocytokines are designed to direct potent immune- modulating factors, such as interferon-alpha (IFN), to the tumor microenvironment to enhance anti-tumor immune responses and tumor-killing activities. We plan, therefore, to explore this combination of technologies to develop NHL-specific immunotherapies using our new panel of BMan9 -targeting mAbs. Specifically, we will determine if humanized polymeric IgGB-Man9 antibodies identify major subtypes of NHLs in tissues and detect CTCs in the blood samples of NHL patients (Aim 1). We will also assess whether anti-BMan9 IgG antibodies and their IFN fusion proteins offer highly efficient killing of the BMan9 - immune types of NHL cells [in vitro and in the A20 mouse models] (Aim 2). [Additionally, we will extend our effort to explore the BMan9-immunotypes of Patient- Derived xenograft (PDX) models for evaluating the therapeutic potential of the Man9-targeting strategy against human NHLs.] Our team has already identified targeting mAbs and established technologies for producing recombinant proteins, and we expect to develop several promising novel NHL-targeting agents during the proposed R21 period. Our work may also reveal the feasibility of exploring other relatively conserved NHL subtype-specific glycan markers that could advance next-generation precision NHL immunotherapy.