TAK-169, a Novel Recombinant Immunotoxin Specific for CD38, Induces Powerful Preclinical Activity Against Patient-Derived Multiple Myeloma Cells

Abstract

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. Disclosures 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.

Novel immunotherapies in multiple myeloma – chances and challenges

“…Preclinical studies demonstrated highly effective lysis of primary MM cells in vitro . 21 No clinical data regarding the ongoing phase I study (NCT04017130) are yet available. TAK-573 targets a CD38 epitope for which cross-reactivity with the currently approved anti-CD38 monoclonal antibodies, daratumumab and isatuximab, is not anticipated.…”

Multiple myeloma: signaling pathways and targeted therapy

“…TAK-169 and TAK-573 are ADCs targeting CD38, which is highly expressed on the surface of MM cells. These ADCs aim to deliver cytotoxic payloads specifically to CD38-expressing cells, thereby inhibiting tumor growth and inducing cell death [ 198 , 199 ]. DFRF4539A is an ADC targeting FcRH5, also known as Fc receptor homolog 5.…”

Antibody–Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?

“…In pre-clinical studies, this agent induced irreversible ribosome inactivation and potent cytotoxicity against CD38-positive human myeloma models [68]. Among tested primary samples, TAK-169 was equally effective against plasma cells from patients with newly diagnosed and relapsed/refractory myeloma, though a fraction of cells from daratumumab-refractory patients were less sensitive [69]. A very preliminary report of the Phase I study in four patients with relapsed/refractory myeloma and at least 5 prior LOT noted one TEAE of asymptomatic Grade 2 reversible myocarditis and Grade 3 troponin elevation [70], raising concern about its further development.…”