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Induction and Impact of Anti-Drug Responses Elicited by a Human Recombinant Coagulation Factor FXaI16L in Preclinical Species

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Abstract

This paper presents a systemic investigation of ADA development and ADA impact of a human coagulation factor in nonclinical species during drug development and provides insights into potential implications in human if a similar ADA occurs. FXaI16L-induced ADA response was characterized in monkey, mouse, rat, and dog in different studies, and ADA effects on pharmacokinetic and/or pharmacodynamics of FXaI16L were further examined in ADA-negative and ADA-positive animals. After repeated administrations, FXaI16L elicited a dose and exposure day-dependent ADA response which ranged from no response to a transient or persistent response. Increase in exposure day and increase in dose generally enhanced ADA incidence except for a decrease in ADA incidence was observed in monkeys after repeated high-dose administrations. The observable ADA impact on pharmacokinetics was only found in some ADA+ animals and included decrease in clearance and increase in systemic exposure but no increase in half-life. In addition, no or limited effect on pharmacodynamics by ADA was observed. The earliest ADA response was observed after three exposure days, marked elevation of drug exposure was observed in some animals at log titer > 2.0, and the highest antibody titer excited was about 4 (Log10) in all species. A correlation between ADA induction and accumulative exposure after various repeat treatments in different species was found for FXaI16L. In addition, potential immunogenicity risk and mitigation of ADA in clinics are discussed.

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Abbreviations

ADA:

Anti-drug antibody

AUC:

Area under the curve

Cmax:

Maximum observed concentration

EGRCK:

Glu-Gly-Arg-chloromethyl ketone

FEIBA:

Factor eight inhibitor bypassing agent (anti-inhibitor coagulant complex)

FXa:

Active coagulation factor X

nAb:

Neutralizing antibody

PK:

Pharmacokinetics

PD:

Pharmacodynamics

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Acknowledgements

All of the authors are Pfizer employees and FXaI16 is a Pfizer clinical candidate. We thank all the support and guidance from the Pfizer FXaI16L development team. We also thank all the colleagues involved in development of FXaI16L in Pfizer whose dedication made all the studies possible.

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Author notes

  1. Chuenlei Parng

    Present address: Pfizer Biomedicine Design, Pharmacokinetics Pharmacodynamics Metabolism, 610 Main St., Cambridge, Massachusetts, 02139, USA

Authors and Affiliations

  1. Pfizer Biomedicine Design, Pharmacokinetics Pharmacodynamics Metabolism, 610 Main St., Cambridge, Massachusetts, 02139, USA

    Rob Webster

  2. Pfizer Drug Safety Research and Development, Cambridge, Massachusetts, 02139, USA

    Michael Bolt

  3. Pfizer Rare Disease Research Unit, Cambridge, Massachusetts, 02139, USA

    Debra D. Pittman

  4. Pfizer Biomedicine Design, Andover, Massachusetts, 01810, USA

    Teresa Caiazzo, Lisa Dyleski & Boris Gorovits

Authors
  1. Chuenlei Parng
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  2. Michael Bolt
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  3. Debra D. Pittman
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  4. Teresa Caiazzo
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  5. Lisa Dyleski
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  6. Boris Gorovits
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  7. Rob Webster
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Correspondence to Chuenlei Parng.

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Parng, C., Bolt, M., Pittman, D.D. et al. Induction and Impact of Anti-Drug Responses Elicited by a Human Recombinant Coagulation Factor FXaI16L in Preclinical Species. AAPS J 21, 52 (2019). https://doi.org/10.1208/s12248-019-0324-z

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