Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies

Our plain-English summary of Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies, by T.K. Kishimoto (Frontiers in Immunology, 2020).

The study

• Author: T.K. Kishimoto
• Journal: Frontiers in Immunology
• Published: 2020;11:969
• Type of article: Review
• Cited by: 50 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The development of anti-drug antibodies (ADAs) is a common cause for treatment failure and hypersensitivity reactions for many biologics. The focus of this review is the development of ImmTOR, a platform technology designed to prevent the formation of ADAs that can be applied broadly across a wide variety of biologics by inducing immunological tolerance with ImmTOR nanoparticles encapsulating rapamycin. The induction of tolerance is antigen-specific and dependent on the incorporation of rapamycin in nanoparticles and the presence of the antigen at the time of administration of ImmTOR. Evidence for the induction of specific immune tolerance vs. general immune suppression is supported by the findings that: (1) ImmTOR induces regulatory T cells specific to the co-administered antigen; (2) tolerance can be transferred by adoptive transfer of splenocytes from treated animals to naïve recipients; (3) the tolerance is durable to subsequent challenge with antigen alone; and (4) animals tolerized to a specific antigen are capable of responding to an unrelated antigen. ImmTOR nanoparticles can be added to new or existing biologics without the need to modify or reformulate the biologic drug. The ability of ImmTOR to mitigate the formation of ADAs has been demonstrated for coagulation factor VIII in a mouse model of hemophilia A, an anti-TNFα monoclonal antibody in a mouse model of inflammatory arthritis, pegylated uricase in hyperuricemic mice and in non-human primates, acid alpha-glucosidase in a mouse model of Pompe disease, recombinant immunotoxin in a mouse model of mesothelioma, and adeno-associated vectors in a model of repeat dosing of gene therapy vectors in mice and in non-human primates. Human proof-of concept for the mitigation of ADAs has been demonstrated with SEL-212, a combination product consisting of ImmTOR + pegadricase, a highly immunogenic enzyme therapy for the treatment of gout. ImmTOR represents a promising approach to preventing the formation of ADAs to a broad range of biologic drugs.

Copyright © 2020 Kishimoto.

In plain English

This was a narrative review written by a single author, an employee and shareholder of Selecta Biosciences, describing the development of ImmTOR — synthetic biodegradable PLA and PLA-PEG nanoparticles encapsulating rapamycin — intended to prevent anti-drug antibodies (ADAs) against biologic drugs. It summarised earlier preclinical work, mostly in inbred laboratory mice with some non-human primate work, and early clinical data. Among the studies reviewed: mice treated with ImmTOR plus keyhole limpet hemocyanin were still seronegative after three challenge injections of the protein alone, whereas mice given daily free rapamycin responded; seven weekly co-administrations with adalimumab mitigated ADAs through nine further injections; five weekly co-administrations with factor VIII gave mitigation maintained at least 5 months in haemophilia A mice; in a mouse mesothelioma model ImmTOR with the LMB-100 immunotoxin mitigated ADAs and was reported to control tumour growth and improve survival, but in mice pre-sensitised with 12 injections titres fell only about 5 to 10-fold. A Phase 1b trial of ImmTOR plus pegadricase showed dose-dependent inhibition of uricase-specific ADAs. The author concluded ImmTOR is a promising approach to mitigating immunogenicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review by a single author (industry-affiliated), covering preclinical animal studies and early clinical data on ImmTOR nanoparticles
• Who was studied: studies in laboratory mice (including hemophilia A, inflammatory arthritis, Pompe disease, mesothelioma tumour and uricase-deficient models), non-human primates, and patients with hyperuricemia or chronic gout in Phase 1b and Phase 2 trials in the United States
• Exposure: ImmTOR (formerly SVP-rapamycin): PLA and PLA-PEG nanoparticles encapsulating rapamycin, given with or encapsulating biologic antigens such as factor VIII, adalimumab, pegadricase, alglucosidase alfa, LMB-100 immunotoxin and AAV vectors
• Main results:
  • In mice given KLH, those treated with ImmTOR plus KLH remained seronegative after three challenge injections of KLH alone, while mice treated with free rapamycin plus KLH developed an antibody response indistinguishable from naive mice
  • In transgenic mice expressing human TNFalpha, ImmTOR co-administered with adalimumab for 7 weekly injections mitigated ADA formation, sustained after 9 further weekly adalimumab-only injections
  • In hemophilia A mice, five weekly co-administrations of ImmTOR with therapeutic doses of free factor VIII gave mitigation of ADAs maintained for at least 5 months despite repeated factor VIII challenges
  • In a mouse mesothelioma model treated with the mesothelin-targeted immunotoxin LMB-100, the author reports that reducing immunogenicity allowed repeated dosing, control of tumour growth and improved survival, including in pre-sensitised mice
  • In mice pre-sensitised with 12 injections of LMB-100 to high ADA titres (about 10,000 to 30,000), subsequent treatment with ImmTOR plus LMB-100 reduced titres only about 5 to 10-fold
  • In a mouse model of Pompe disease, ImmTOR with alglucosidase alfa gave more durable inhibition of ADA formation, higher skeletal muscle glycogen clearance and improved motor function than methotrexate, but anti-GAA antibody titres developed by 12 weeks
  • In the Phase 1b trial (NCT02648269) of ImmTOR plus pegadricase in patients with hyperuricemia, adding ImmTOR produced dose-dependent inhibition of ADA formation
  • In the same Phase 1b trial, among patients given pegadricase alone, serum uric acid rebounded so that 4 of 5 were back to baseline by day 30, and all developed high ADA titres by day 14
• The authors' conclusion: The author concluded that ImmTOR nanoparticles are a promising approach to mitigating the immunogenicity of a wide range of biologics without reformulating them, and that further study is warranted
• Limitations the authors state:
  • The author states most preclinical work used inbred laboratory mice, with obvious limitations for translating findings to humans
  • The author states the two ImmTOR factor VIII approaches used different regimens and challenge injections, so their results cannot be directly compared
  • The author states the effect of ImmTOR on the anti-tumour activity of the checkpoint inhibitors was not investigated
  • The author states the ability of ImmTOR to mitigate pre-existing antibody titres may vary with the antigen and the level of pre-existing antibodies
  • Declared conflict of interest: the author is an employee and shareholder of the company developing ImmTOR, which funded the work

Topics

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Mesothelioma.

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