No lack of potential for NK cells
HEIDELBERG, Germany—The 58th American Society of Hematology (ASH) Annual Meeting and Exposition 2016 saw biopharmaceutical company Affimed N.V. present posters on a trio of studies regarding its work with various antibodies and T cell-focused compounds.
One of the posters was presented with the German Cancer Research Center (DKFZ), Affimed’s collaboration partner, regarding the mechanism of action of lead product candidate AFM13, a CD30/CD16A-specific natural killer (NK) cell engager. Previous studies have shown that combining AFM13 with checkpoint modulation such as anti-PD-1 offers synergistic efficacy, and this latest work expands on it by identifying biomarkers and other potential candidates for additional combination therapies.
In a press release, Affimed noted that AFM13 was found to significantly increase NK cell cytotoxicity toward CD30+ tumor cells and IFN-γ production in vitro, and proved much more potent than a native anti-CD30 IgG1 antibody. Further analysis showed that interaction of NK cells with AFM13-coated tumor cells led to the up-regulation of the expression of NK cell surface receptors such as CD25, CD69 and CD137/4-1BB, as well as other markers that could serve as NK cell checkpoints. In addition, AFM13-mediated CD16A engagement boosted NK cells’ potential for proliferation and expansion when incubated with the cytokines IL-15 or IL-2, a result that was seen even in target cells resistant to naïve NK cells and to NK cells activated only with IL-2/IL-15.
Back in October, the company made a presentation on AFM13 at 16th Annual Meeting of the Society for Natural Immunity in Taormina, Italy, the data for which were gathered in collaboration with the Innate Immunity Group of Dr. Adelheid Cerwenka at the DKFZ. AFM13 was found to bolster NK cell cytotoxicity against CD30+ tumor cells that are resistant to naïve NK cells. Specifically, it boosts cytokine-mediated NK cell proliferation and expansion by enhancing the NK cells’ sensitivity to IL-2 and IL-15.
“A common theme in all different cancer types is the ability of the tumor cells to evade recognition by immune cells. AFM13 is able to fix this problem as it reattaches a natural killer cell to the tumor which initiates the killing and elimination process. Furthermore, engaging NK cells may offer the unique opportunity to activate both innate and adaptive immunity,” say Drs. Adi Hoess and Martin Treder, Affimed’s CEO and CSO, respectively.
A second poster at the ASH meeting was presented with collaboration partners from University Hospital Wuerzburg, highlighting the researchers’ findings on how treatment history affects T cell engagement. The team analyzed the activity of the CD19/CD3-specific TandAb AFM11 on T cells taken from non-Hodgkin’s lymphoma (NHL) patients after different chemotherapeutic regimens (R-Bendamustine, R-CHOP and HD-BEAM) compared to T cells from healthy donors. Patient T cell levels were noticeably lower post-chemotherapy and presented with functional defects, but AFM11 proved capable of activating them for potent target cell lysis with comparable efficacy to T cells from healthy donors. The specific type of chemotherapy a patient has had also proved to affect AFM11-mediated T cell engagement: T cells from patients who underwent treatment with R-CHOP demonstrated responsiveness like that of T cells from healthy donors; the cells from patients treated with R-Bendamustine and HD-BEAM saw lower cytotoxic activity.
Affimed presented a third poster at the conference as well, this one on its trispecific antibody format when applied to a multiple myeloma model system. The company’s TandAbs are tetravalent antibodies with bivalent binding to both cancer and immune cells. Trispecific tetravalent antibodies have been designed that can redirect NK cells to tumor cells co-expressing two surface antigens (“dual- targeting”), which offers increased tumor cell selectivity. B-cell maturation antigen (BCMA/CD269) has a largely tumor cell-specific expression profile, which makes it a solid target antigen for antibody-based therapies for multiple myeloma.
For this work, Affimed chose CD200 as the second multiple myeloma-expressed surface antigen found in the majority of patients. Trispecific antibodies selectively engaged NK cells in vitro via bivalent binding to CD16A and monovalent binding to BCMA and CD200. Binding to BCMA+/CD200+ cells led to an increase in avidity (the bond strength between antibodies and antigens), which led to preferential lysis of antigen double-positive cells compared with antigen single-positive cells. Taken together, the data suggest that dual-targeting could increase the therapeutic window compared to approaches that only target a single antigen.
Affimed’s focus remains on NK cell-based approaches, Hoess and Treder tell DDNews, as the company is currently investigating AFM13 as a monotherapy and in combination with other therapies in Hodgkin lymphoma, with AFM11 in Phase 1 development in NHL and ALL.
“Despite the successes with chemotherapeutics, there is a high medical need for improved therapies with fewer side effects and long-term or even curative results, and this is where immunotherapy comes in,” Hoess and Treder comment.