Compositions and methods to mitigate or prevent an immune response to an immunogenic therapeutic molecule in non-human primates

a technology of immunogenic therapeutic agents and compounds, which is applied in the field of immunology and modulating the response to immunogenic therapeutic agents, can solve the problems of triggering anaphylaxis or death of animals, affecting the safety profile of products in humans, and affecting the safety of products, so as to reduce the probability of an incidence of ada, mitigate the formation of ada in a nhp, and reduce the intensity of ada

Inactive Publication Date: 2017-06-08
JOMOCO CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]In some embodiments, administration of an immunosuppressant to an NHP as described herein decreases the probability of an incidence of ADA against an immunogenic therapeutic molecule. In some embodiments, administration of an immunosuppressant as described herein decreases the intensity of ADA formation against an immunogenic therapeutic molecule. In some embodiments, administration of an immunosuppressant to an NHP mitigates the formation of ADA in a NHP.
[0020]In some embodiments, administration of an IL-2 pathway inhibitor as described herein decreases the probability of an incidence of ADA against an immunogenic therapeutic molecule. In some embodiments, administration of an ...

Problems solved by technology

Because the immune system of different species can distinguish orthologous proteins as foreign, the preclinical testing of human therapeutic proteins in non-human species can be dramatically hampered by the animals' immune response to the protein, resulting in antibody-mediated al...

Method used

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Examples

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Effect test

example 1

[0143]Administration of a basiliximab loading dose on Day 0 of the NHP preclinical pharmacokinetic study is followed on Day 1 by administration of a basiliximab maintenance dose and the potentially immunogenic therapeutic agent. Basiliximab is dosed approximately every 10 days to maintain a serum concentration at which CD25 is almost completely bound by basiliximab (about 200 ug / mL). The therapeutic agent is dosed at the proscribed interval and dose. In a control group to which the therapeutic agent but not basiliximab is administered, the pharmacokinetic parameters of the therapeutic agent are altered (increased or decreased) due to the development of ADA in some or all of the animals. In the basiliximab treated group, no ADA develops or the level of ADA is sufficiently low such that the pharmacokinetic parameters of the therapeutic agent are unaltered. Because the basiliximab treated NHP do not develop ADA, they may be used in another study with the same or a different potentially...

example 2

[0144]Administration of a basiliximab loading dose on Day 0 of the NHP toxicology study is followed on Day 1 by administration of a basiliximab maintenance dose and the potentially immunogenic therapeutic agent. Basiliximab is dosed approximately every 10 days to maintain a serum concentration at which CD25 is almost completely bound by basiliximab (about 200 ug / mL). The therapeutic agent is dosed at the proscribed interval and dose. In the group administered basiliximab and the therapeutic agent, the animals develop immune mediated drug induced liver injury (DILI). In the group administered the potentially immunogenic therapeutic agent alone, the development of ADA in some or all of the animals prevents the induction of DILI, thus masking a potentially fatal drug associated toxicity. Because administration of basiliximab prevents the development of ADA and thus unmasks immune DILI mediated by the immunogenic therapeutic agent, further development of the therapeutic agent would be h...

example 3

[0145]Administration of a nanocarrier encapsulated rapamycin (NER) loading dose on Day −2, −1, or 0 of the NHP preclinical pharmacokinetic study is followed on Day 0 by administration the potentially immunogenic therapeutic agent. NER and the therapeutic agent are then co-administered at the proscribed dose and intervals of every 1-4 weeks for as many as 12 weeks, following which the immunogenic therapeutic agent may be administered without NER. In a control group to which the therapeutic agent but not NER is administered, the pharmacokinetic parameters of the therapeutic agent are altered (increased or decreased) due to the development of ADA in some or all of the animals. In the NER treated group, no ADA develops or the level of ADA is sufficiently low such that the pharmacokinetic parameters of the therapeutic agent are unaltered. Because the NER treated NHP do not develop ADA, they may be used in another study with the same or a different potentially immunogenic therapeutic agen...

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Abstract

Methods and compositions for preventing an immune response to an immunogenic therapeutic agent [i.e. anti-drug antibody (ADA), a.k.a. anti-therapeutic antibody (ATA)] are disclosed. One of the disclosed methods comprises administering an effective amount of an immunosuppressant such as an IL-2 signaling pathway inhibitor, including an antagonist, super agonist or partial agonist to the cytokine IL-2, to the IL-2 receptor (IL-2R), or to IL-2R signal transduction molecules. Inhibitors can be in the form of antibodies or antibody fragments, peptide inhibitors, fusion molecule, small molecules, antibody/small molecule conjugates. Administration of a given inhibitor can decrease the incidence and/or magnitude of an immune response or prevent an immune response, including an antibody response, to a potentially immunogenic therapeutic agent in a non-human primate (NHP). Some of the disclosed methods produce a tolerizing effect in NHPs.

Description

RELATED APPLICATIONS[0001]This application claims priority under 35 U.S.C. 119 (e) to U.S. Provisional Patent Application Ser. No. 62 / 263,352, entitled “Compositions and Methods to Mitigate an Immune Response to an Immunogenic Therapeutic Agent in Non-Human Primates (NHP)”, filed Dec. 4, 2015, the disclosure of which is hereby incorporated by reference in its entirety.TECHNICAL FIELD[0002]The present invention is generally in the field of immunology and of modulating responses to immunogenic therapeutic agents.BACKGROUND OF THE INVENTION[0003]Biological medicinal products and therapeutic agents are a growing proportion of tested pharmaceutical drugs. Drug development and licensure entails the testing of these products in several animal species prior to their administration to humans. As non-human primates (NHP) are the species closest to man, they are generally the last animal species in which testing is performed before a drug is administered to humans.[0004]Biological medicinal pr...

Claims

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Application Information

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IPC IPC(8): A61K38/20A61K31/436C07K16/28
CPCA61K38/2013C07K16/2866A61K2039/505C07K2317/76A61K31/436C07K14/7155A61K45/06A61K2300/00
Inventor RAGHEB, JACK A.
Owner JOMOCO CORP
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