title: Immune Suppression During Preclinical Drug Development Mitigates Immunogenicity-Mediated Impact on Therapeutic Exposure.
abstract: In the clinical setting, anti-drug antibodies (ADA) against biotherapeutics can influence patient safety and interfere with product efficacy. High immunogenicity has been addressed in clinic by concomitant immune suppression, such as co-administration of methotrexate with enzyme replacement therapy (ERT) and combination tacrolimus/sirolimus treatment for prophylaxis against organ transplant rejection. This study investigates the use of such immune suppressants in mitigating ADA responses to a fully human monoclonal antibody (mAb1) in preclinical animal studies. Three groups of Sprague Dawley rats (n = 18) were treated with low (0.01 mg/kg), moderate (50 mg/kg), or high (300 mg/kg) doses of mAb1. Experimental groups also received either methotrexate or tacrolimus/sirolimus immune suppressive regimens. ELISA-based methods were utilized to measure and characterize ADA and mAb1 pharmacokinetics (PK). Results demonstrated a stepwise increase in immunogenicity with mAb1 dosage. Methotrexate significantly lowered incidence of anti-variable region antibodies at moderate mAb1 dose (P < 0.05), while tacrolimus/sirolimus did likewise at moderate and high doses (P < 0.01) of mAb1. Except for low-dose mAb1 + methotrexate, all immunosuppressed groups displayed more than a 70-fold decrease in ADA magnitude (P < 0.05). This abrogation in ADA response correlated with more mAb1 in circulation by week 4 for moderate- and high-dosed mAb1 groups. These data provide an approach to mitigate preclinical immunogenicity by the use of immunosuppressant regimens. Such preconditioning can support preclinical drug development of human therapeutics that are antigenic to animals. Similar approaches could be investigated for wider application to novel therapeutics.
authors.affiliation: The Department of Medical Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, California, 91320, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Herskovitz
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Josiah
authors.initials: J
authors.lastname: Ryman
authors.affiliation: The Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, 91320, USA.
authors.forename: Theingi
authors.initials: T
authors.lastname: Thway
authors.affiliation: The Department of Medical Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, California, 91320, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lee
authors.affiliation: The Department of Medical Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, California, 91320, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: The Department of Medical Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, California, 91320, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Chirmule
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
authors.affiliation: The Department of Medical Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, California, 91320, USA. vibha.jawa@merck.com.
authors.forename: Vibha
authors.initials: V
authors.lastname: Jawa
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate
keywords: immune suppression; immunogenicity; preclinical; risk mitigation