Anti-IL21 receptor monoclonal antibody (ATR-107): Safety, pharmacokinetics, and pharmacodynamic evaluation in healthy volunteers: A phase 1, first-in-human study

Journal of Clinical Pharmacology

Volumn 54, Issue 1, 2014, Pages 14-22

  Hua, Fei ^a   Comer, Gail M ^a,b   Stockert, Lori ^a   Jin, Bo ^a   Nowak, John ^a   Pleasic Williams, Susan ^a   Wunderlich, David ^a   Cheng, John ^a   Beebe, Jean S ^a  

^a PFIZER INC   (United States)

^b Synergy Pharmaceuticals   (United States)

Author keywords

Anti drug antibody; First in human; Hypersensitivity; IL 21; Immunogenicity; Pharmacodynamics; Pharmacokinetics; Receptor occupancy

Indexed keywords

ATR 107; INTERLEUKIN 21 RECEPTOR; MONOCLONAL ANTIBODY; PLACEBO; UNCLASSIFIED DRUG;

ADULT; APPLICATION SITE IRRITATION; AREA UNDER THE CURVE; ARTICLE; B LYMPHOCYTE; BLURRED VISION; CREATINE KINASE BLOOD LEVEL; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG ADSORPTION; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG HYPERSENSITIVITY; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG SCREENING; DRUG TOLERABILITY; FEMALE; HEMATOMA; HUMAN; HUMAN EXPERIMENT; IMMUNOGENICITY; INJECTION SITE ERYTHEMA; INJECTION SITE EXTRAVASATION; INJECTION SITE PAIN; INJECTION SITE PRURITUS; INJECTION SITE REACTION; INJECTION SITE SWELLING; LIMIT OF QUANTITATION; MALE; MAXIMUM PLASMA CONCENTRATION; MIDDLE AGED; MULTICENTER STUDY; MUSCULOSKELETAL CHEST PAIN; NORMAL HUMAN; OROPHARYNX PAIN; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; PRURITUS; RECEPTOR OCCUPANCY; SINGLE DRUG DOSE; TIME TO MAXIMUM PLASMA CONCENTRATION; UPPER RESPIRATORY TRACT INFECTION; VIRAL UPPER RESPIRATORY TRACT INFECTION; YOUNG ADULT;

ANTI-DRUG ANTIBODY; FIRST IN HUMAN; HYPERSENSITIVITY; IL-21; IMMUNOGENICITY; PHARMACODYNAMICS; PHARMACOKINETICS; RECEPTOR OCCUPANCY;

ADOLESCENT; ADULT; ANTIBODIES, MONOCLONAL; BIOLOGICAL AVAILABILITY; COHORT STUDIES; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; ELECTROCARDIOGRAPHY; FEMALE; HALF-LIFE; HUMANS; INJECTIONS, INTRAVENOUS; INJECTIONS, SUBCUTANEOUS; MALE; MIDDLE AGED; RECEPTORS, INTERLEUKIN-21; YOUNG ADULT;

EID: 84893256472     PISSN: 00912700     EISSN: 15524604     Source Type: Journal    
DOI: 10.1002/jcph.158     Document Type: Article

References (19)

1. Parrish-Novak J, Dillon SR, Nelson A, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408(6808):57-63.
2. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 2008;26:57-79.
3. Swann JB, Coquet JM, Smyth MJ, Godfrey DI. CD1-restricted T cells and tumor immunity. Curr Top Microbiol Immunol. 2007;314: 293-323.
4. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Natl Acad Sci USA. 2000;97(21):11439-11444.
5. Jin H, Carrio R, Yu A, Malek TR. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J Immunol. 2004;173(1):657-665.
6. Brandt K, Bulfone-Paus S, Foster DC, Ruckert R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood. 2003; 102(12):4090-4098.
7. Pelletier M, Bouchard A, Girard D. In vivo and in vitro roles of IL-21 in inflammation. J Immunol. 2004;173(12):7521-7530.
8. Ettinger R, Kuchen S, Lipsky PE. The role of IL-21 in regulating Bcell function in health and disease. Immunol Rev. 2008;223:60-86.
9. Rankin AL, MacLeod H, Keegan S, et al. IL-21 receptor is critical for the development of memory B cell responses. J Immunol. 2011;186(2):667-674.
10. Yoshizaki A, Miyagaki T, DiLillo DJ, et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature. 2012;491(7423):264-268.
11. Ettinger R, Kuchen S, Lipsky PE. Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis. 2008;67(Suppl 3):iii83-iii86.
12. Monteleone G, Monteleone I, Fina D, et al. Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. Gastroenterology. 2005;128(3):687-694.
13. Young DA, Hegen M, Ma HL, et al. Blockade of the interleukin- 21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum. 2007;56(4):1152- 1163.
14. Rankin AL, Guay H, Herber D, et al. IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice. J Immunol. 2012;188(4):1656- 667.
15. Herber D, Brown TP, Liang S, et al. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R. Fc reduces disease progression. J Immunol. 2007;178(6):3822-3830.
16. Vugmeyster Y, Guay H, Szklut P, et al. In vitro potency, pharmacokinetic profiles, and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus. MAbs. 2010; 2(3):335-346.
17. Zhu M, Pleasic-Williams S, Lin TH, et al. pSTAT3: a target biomarker to study the pharmacology of the anti-IL-21R antibody ATR-107 in human whole blood. J Transl Med. 2013;11(1):65.
18. Pleasic-Williams S, Wunderlich D, Masferrer J, Hua F, Cheng J. Qualification of a human blood pSTAT3 assay for analysis of clinical samples: an involvement of its nuclear translocation in CD4+ cells, in 27th Annual Clinical Cytometry. 2012. New Orleans, LA.
19. Ozaki K, Spolski R, Feng CG, et al. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298(5598): 1630-1634.