A Reduction in B, T, and Natural Killer Cells Expressing CD38 by TAK-079 Inhibits the Induction and Progression of Collagen-Induced Arthritis in Cynomolgus Monkeys.

Wouter Korver,Eric R Fedyk,Matthew Wagoner,Mary Carsillo,Neeraja Idamakanti,Josh Yuan,Lachy Mclean,Glennda Smithson,Pu Shi,Cindy Q Xia,Jonathan Zalevsky

doi:10.1124/jpet.119.256602

Wouter Korver, Eric R Fedyk + Show 9 more

Open Access

https://doi.org/10.1124/jpet.119.256602

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Abstract

Ectoenzyme CD38 is increased on lymphocytes in response to an antigenic challenge and it is hypothesized that targeting these activated lymphocytes could ameliorate pathologic activities in autoimmune diseases. The cynomolgus monkey is an appropriate model for assessing potential effects of targeting CD38 in humans because these species exhibit similar expression profiles. TAK-079 is a human monoclonal antibody (IgG1 λ ) that binds to CD38 and lyses bound cells by complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. TAK-079 binds to monkey CD38 with an affinity at EC50 4.5 nM, and the potential activity of TAK-079 was investigated in a monkey collagen-induced arthritis model of autoimmune disease. Prophylactic administration of TAK-079 (3 mg/kg i.v. weekly) was well tolerated and prevented arthritis development compared with vehicle-treated control animals, which exhibited progressive disease with radiographic damage and worsening clinical scores over the study course. Therapeutic treatment of arthritic monkeys with TAK-079 (3 mg/kg i.v. weekly) was also well tolerated and reduced disease progression and symptoms. Arthritis scores and joint swelling were significantly lower than the vehicle control, accompanied by decreases in blood levels of C-reactive protein, alkaline phosphatase, and natural killer, B, and T cells. Histopathology, morphometry, and radiology revealed significantly less joint damage in animals exposed prophylactically to TAK-079 treatment compared with vehicle-treated animals and significantly less damage in animals treated therapeutically with TAK-079 or dexamethasone (0.1 mg/kg oral gavage daily), illustrating potential disease-modifying activity. In conclusion, these data indicate that depletion of CD38-expressing cells could be a therapeutic mechanism for treating autoimmune diseases. SIGNIFICANCE STATEMENT: This study demonstrates that targeting CD38-expressing leukocytes with a cytolytic antibody can ameliorate autoimmune disease in cynomolgus monkeys. The study gives a unique perspective into this therapeutic strategy because the three other anti-CD38 cytolytic antibodies in clinical development (daratumumab, isatuximab, and MOR202) cannot be tested in similar models because they do not crossreact with CD38 expressed by new world primates.

Highlights

Autoantibodies mediate the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA) (Deane, 2014) and systemic lupus erythematosus (SLE) (Kurts et al, 2013), directly by binding to tissue antigens and indirectly via the deposition of immune complexes (Martin and Chan, 2006)
To determine if the cynomolgus monkey could be an adequate model for assessing the potential effects of targeting CD38 in humans, the expression profile of the CD38 antigen was compared across 15 different types of tissues collected from healthy human and cynomolgus monkey donors
In contrast to other antiCD38 monoclonal antibody (mAb) in development, TAK-079 binds to CD38 expressed by cynomolgus monkeys and provides the unique opportunity to determine if reducing the levels of cells expressing CD38 would prevent and/or ameliorate inflammation and tissue damage in a nonhuman primate model of autoimmunity

Summary

Introduction

Autoantibodies mediate the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA) (Deane, 2014) and systemic lupus erythematosus (SLE) (Kurts et al, 2013), directly by binding to tissue antigens and indirectly via the deposition of immune complexes (Martin and Chan, 2006) These autoantibodies are produced by transient, short-lived plasmablasts and plasma cells in secondary lymphoid tissues and by long-lived plasma cells and are entrenched in supportive niches within the bone marrow (Radbruch et al, 2006; Nutt et al, 2015). Most existing therapeutics affect plasma cells and antibody production indirectly by modulating progenitors of these cells, e.g., rituximab (anti-CD20) targets B lymphocytes and belimumab inhibits short-lived plasmablasts from proliferation (Hale et al, 2018) Both methods can reduce autoantibody production; this effect manifests slowly (e.g., months to years) (Stohl et al, 2012) because of the relatively long half-life of pre-existing plasma cells. Gastrointestinal and neurologic adverse events restrict the use of bortezomib

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