Monoclonal antibodies (daratumumab, anti-CD38; elotuzumab, anti-SLAMF7) and BCMA-targeting T-cell redirecting therapies are highly effective in a large proportion of multiple myeloma (MM) patients. Nonetheless, age, prior (chemo)therapy, and the tumor-microenvironment may impair immune effector cell function and therefore significantly reduce the efficacy of these immunotherapies. Alternatively, an appealing strategy would be the use of targeted therapies, such as immunoconjugates, that directly kill the tumor cells. TAK-169, a novel CD38-specific immunotoxin armed with a deimmunized (DI) Shiga-like toxin A subunit (SLTA) payload, has been designed with this idea. TAK-169 induces irreversible ribosome inactivation of target cells with no dependency on immune effector cells. Prior studies showed that TAK-169 exerts potent cytotoxic activity against CD38-positive human MM cell lines in vitro and in xenograft mouse models (Willert et al. AACR 2019 Abstract 2384). Also, TAK-169 was well tolerated in mice and non-human primates (Willert et al. AACR 2019 Abstract 2384), and deimmunizing the SLTA molecule significantly reduced the in vivo immunogenicity of the payload (Willert et al. AACR 2015 Abstract 2477; Rajagopalan et al. AACR 2016 Abstract 595; Robinson et al. AACR 2017 Abstract 2695).
We now assessed the preclinical activity of TAK-169 on a large panel of primary MM cells present in bone marrow (BM) samples from newly diagnosed (ND) (n=13), daratumumab-naive relapsed/refractory (RR) (n=11), and daratumumab-refractory (DR) RR (n=12) patients in flow cytometry-based cytotoxicity assays. In these samples, we also tested the impact of TAK-169 on non-malignant CD38-expressing hematopoietic cells, to gain insight into its on-target off-tumor effects.
TAK-169 effectively lysed MM cells present in 36/36 BM samples in a dose-dependent fashion (Figure 1A; median maximal lysis 89%; range 45-100%; EC50: 36pM). Of note, MM cells from ND and daratumumab-naïve RR patients were equally sensitive to TAK-169-mediated lysis (Figure 1B and 1C; median maximal lysis 90%; range 76-100% vs. median maximal lysis 91%; range 76-98%). While MM cells from DR RR patients were also effectively killed, a fraction of these samples was less sensitive to TAK-169-mediated lysis (Figure 1B and 1C; median maximal lysis 66%, range 45-99%). We are currently exploring the impact of several patient and tumor characteristics, such as previous therapies and surface CD38 expression levels on MM cells, on the cytotoxic activity of TAK-169, and results will be reported. In the BM samples, the cytotoxic activity of TAK-169 was mainly restricted to MM cells - except for limited lysis of NK cells (median maximal lysis: 18%) and monocytes (median maximal lysis: 21%), no other non-malignant hematopoietic cells were lysed (Figure 1D), indicating a favorable therapeutic window generated by targeting CD38 with TAK-169.
In conclusion, we show that TAK-169 induces powerful lysis of primary MM cells from both ND and RR MM patients, including those refractory to daratumumab. Our findings support the ongoing phase 1 clinical trial evaluating TAK-169 monotherapy in heavily pretreated MM (NCT04017130), and encourage preclinical evaluation of TAK-169 in other CD38-positive malignancies such as AML and T-ALL.
Higgins:Molecular Templates, Inc.: Current Employment, Other: Stockholder. Willert:Molecular Templates, Inc.: Current Employment, Other: Stockholder. Newcomb:Takeda Pharmaceuticals International: Current Employment, Other: Stockholder. Dash:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment, Other: Stockholder. Van De Donk:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mutis:Gadeta: Research Funding; Onkimmune: Research Funding; Takeda: Research Funding; Janssen Pharmaceuticals: Research Funding; Genmab: Research Funding.
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