Immune Suppression During Preclinical Drug Development Mitigates Immunogenicity-Mediated Impact on Therapeutic Exposure

Jonathan Herskovitz, Josiah Ryman, Theingi Thway, Stephanie Lee, Lei Zhou, Narendra Chirmule, Bernd Meibohm, Vibha Jawa

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)447-455
Number of pages9
JournalAAPS Journal
Volume19
Issue number2
DOIs
StatePublished - Mar 1 2017

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Anti-Idiotypic Antibodies
Methotrexate
Tacrolimus
Sirolimus
Pharmaceutical Preparations
Antibody Formation
Therapeutics
Enzyme Replacement Therapy
Graft Rejection
Human Development
Patient Safety
Immunosuppressive Agents
Sprague Dawley Rats
Pharmacokinetics
Enzyme-Linked Immunosorbent Assay
Monoclonal Antibodies
Transplants
Antibodies
Incidence

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Immune Suppression During Preclinical Drug Development Mitigates Immunogenicity-Mediated Impact on Therapeutic Exposure. / Herskovitz, Jonathan; Ryman, Josiah; Thway, Theingi; Lee, Stephanie; Zhou, Lei; Chirmule, Narendra; Meibohm, Bernd; Jawa, Vibha.

In: AAPS Journal, Vol. 19, No. 2, 01.03.2017, p. 447-455.

Research output: Contribution to journalArticle

Herskovitz, Jonathan ; Ryman, Josiah ; Thway, Theingi ; Lee, Stephanie ; Zhou, Lei ; Chirmule, Narendra ; Meibohm, Bernd ; Jawa, Vibha. / Immune Suppression During Preclinical Drug Development Mitigates Immunogenicity-Mediated Impact on Therapeutic Exposure. In: AAPS Journal. 2017 ; Vol. 19, No. 2. pp. 447-455.
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