title: Pharmacokinetic, Pharmacodynamic, and Safety Profile of a Novel Anti-CD28 Domain Antibody Antagonist in Healthy Subjects.
abstract: We report pharmacokinetics, pharmacodynamics, and safety of a novel anti-CD28 domain antibody antagonist (lulizumab pegol) in healthy subjects following single- or multiple-dose administration. A minimal anticipated biological effect level approach was used to select a 0.01 mg starting dose for a single-ascending-dose (SAD), double-blind, first-in-human study. Part 1 included 9 intravenous (IV; 0.01-100 mg) and 3 subcutaneous (SC; 9-50 mg) doses or placebo. In part 2, a keyhole limpet hemocyanin (KLH) immunization was performed in 16 subjects/panel, who received 1 of 3 IV doses (9-100 mg) or placebo. In a double-blind, multiple-ascending-dose (MAD) study, subjects received SC lulizumab 6.25 mg every 2 weeks, 12.5 mg weekly, 37.5 mg weekly, or placebo. Among 180 treated subjects, 169 completed the studies. Peak concentrations and areas under the curve from time 0 to infinity increased dose proportionally. Estimated SC bioavailability was 68.2%. Receptor occupancy of approximately ≥80% was maintained for ≥2 weeks at ≥9-mg doses (SAD) and throughout the dosing interval (MAD). IV doses ≥9 mg inhibited antibody production against KLH for 2 weeks. No significant cytokine or immune cell changes were observed. No immunogenicity responses persisted, and there was no correlation to adverse events. Headache occurred in 21 SAD and 4 MAD subjects receiving lulizumab; in the MAD study 5 lulizumab subjects experienced infections. Lulizumab IV or SC was safe at all doses studied, without evidence of cytokine release.
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Shi
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Marek
authors.initials: M
authors.lastname: Honczarenko
authors.affiliation: GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fleener
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mora
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Sun Ku
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Xiaoni
authors.initials: X
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Shevell
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Murthy
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000009:adverse effects; D019138:Antibodies, Blocking / Q000009:adverse effects / Q000378:metabolism*; D001682:Biological Availability; D018106:CD28 Antigens / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006261:Headache / Q000139:chemically induced; D064368:Healthy Volunteers; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics*; D011971:Receptors, Immunologic / Q000187:drug effects; D055815:Young Adult
chemical_list: D000906:Antibodies; D019138:Antibodies, Blocking; D018106:CD28 Antigens; D016207:Cytokines; D011971:Receptors, Immunologic; D011092:Polyethylene Glycols; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; C000604694:lulizumab pegol
keywords: biologics; clinical trials (CTR); immunopharmacology (imm); pharmacodynamics (PDY); pharmacokinetics and drug metabolism; rheumatology