TAK-573, an Anti-CD38/Attenuated Ifnα Fusion Protein, Has Clinical Activity and Modulates the Ifnα Receptor (IFNAR) Pathway in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Vogl Dan T. , Kaufman Jonathan L. , Holstein Sara A. , Nadeem Omar , O'Donnell Elizabeth , Suryanarayan Kaveri , Collins Sabrina , Parot Xavier , Chaudhry Maria 
Published: February 2021

Background:
TAK-573 is a first-in-class, humanized, anti-CD38, IgG4 monoclonal antibody genetically fused to 2 attenuated interferon alpha-2b (IFNα2b) molecules. The specificity for CD38 and reduced binding affinity of the attenuated IFNα molecules significantly reduces the potential for off-target toxicity. TAK-573 binds to a site on CD38 that is distinct from the binding sites of currently available therapeutic antibodies, and therefore does not compete for binding with daratumumab or isatuximab. Non-clinical studies have shown that TAK-573 has robust anti-tumor activity, including complete responses, in MM xenograft models.
Patients and Methods:
The first in human phase I trial (NCT03215030) enrolled patients (pts) with relapsed or refractory multiple myeloma (RRMM) after at least 3 previous lines of treatment. Pts received TAK-573 as a 1 to 4-hour IV infusion in 11 dose levels from 0.001 to 3 mg/kg. The initial schedule was weekly for 8 doses, then every 2 weeks for 8 doses, and then monthly. Subsequent cohorts are also exploring dosing once every 2 (Q2), every 3 (Q3) or every 4 weeks (Q4).
Peripheral blood (PB) and bone marrow (BM) aspirates were collected before and after TAK-573 dosing. CD38 receptor occupancy (RO) and receptor density (RD) were determined using 9-color flow cytometry. Serum samples were analyzed using the Immuno-Oncology panel of Olink's proximity extension assay platform to measure changes in cytokine and chemokine levels. Whole transcriptome sequencing of bulk RNA was performed to determine the type I interferon (IFN) gene signature induction. Mass cytometry-based immunophenotyping was utilized to characterize changes in immune cell prevalence and activation status of cryopreserved cells from both the PB and BM.
Results:
As of June 2020, 59 patients had been treated on all schedules. The median number of prior lines of therapy was 7 (range: 3-20); 93% had received at least 1 daratumumab-containing regimen, and 14% had received previous CAR-T cell therapy. Thrombocytopenia was the most frequent TEAE (83%) and was Grade ≥3 in 28 (47%) pts. Prolonged thrombocytopenia was a dose limiting toxicity (DLT) in 7 pts, but was not associated with clinical bleeding, and 9 pts required platelet transfusions. Neutropenia was reported as a TEAE in 54% of pts (Grade ≥3 in 49% pts), and was a DLT in 4 patients, including one pt who had febrile neutropenia. The maximum tolerated dose for the initial schedule was 0.1 mg/kg, and evaluation of other schedules is ongoing. Myeloma responses have been observed starting at doses of 0.1 mg/kg on the initial schedule, 0.4 mg/kg q2 weeks, and 1.5 mg/kg q4 weeks (as shown in Table 1).
Single administration of TAK-573 resulted in a dose dependent increase in CD38 RO of PB-derived immune cells, with saturation of CD38 RO 4 hours after the end of infusion (EOI) at doses ≥ 0.2 mg/kg. The duration of saturation was dose dependent, with doses ≥ 0.75 mg/kg TAK-573 saturating CD38 RO through 24 hours. CD38 RO in BM samples showed similar results, with added variability due to the timing of sample collection and individual patients' tumor burden. At all dose levels, TAK-573 administration resulted in increases in the type I IFN gene signature 24 hours after the dose. As CD38 is an IFN-stimulated gene, TAK-573 treatment resulted in CD38 RD increases, most notably on NK cells but also on other CD38 positive cells, including MM cells within the BM. BM MM cells also showed decreases in complement-inhibitory proteins CD55 and CD59 after TAK-573 treatment. Circulating levels of IFN-associated chemokines (IFNγ, CXCL10, MCP-1 and IL-15) also increased, with maximal induction 4 hours after EOI. CD69 expression, a marker of early activation, increased on BM CD8+ T cells in 7 of 9 patients analyzed; the CD8+ T-cells for 3 of those 7 patients also showed increases in IFNγ positivity, indicating that TAK-573 treatment can increase the cytolytic potential of CD8+ T-cells in the BM of a subset of patients.
Conclusion:
TAK-573 is a clinically and pharmacologically active molecule that mediates IFNAR pathway modulation and leads to myeloma responses. Additional biomarker data is being collected to further refine the MOA, which will inform the recommended phase 2 dose, optimal schedule of administration, and rational development of TAK-573.

Disclosures
Vogl: Active Biotech: Consultancy, Research Funding; Takeda: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Oncopeptides: Consultancy; MorphoSys: Consultancy. Kaufman:Takeda: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Tecnopharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy. Holstein:GSK: Consultancy; Celgene: Consultancy; Sorrento: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy. Nadeem:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Suryanarayan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Collins:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Parot:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Chaudhry:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
TAK-573 is a first-in-class, humanized, anti-CD38, IgG4 monoclonal antibody genetically fused to 2 attenuated interferon alpha-2b (IFNÃŽÂ±2b) molecules