Immunogenicity of Gene Therapies

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The immune response can be divided into innate and adaptive immunity3

The innate and adaptive immune responses work together4

Innate Immune Response

Initiates within hours post-infection5

The innate immune response is rapid, non-specific, and develops hours after an infection.4,5 It is crucial for the initiation of an adaptive immune response4

Responses 4,6

  • First line of defense
  • Non-specific response
  • Phagocytosis
  • Inflammation and fever
  • Crucial for initiation of adaptive immune response

Effectors 4,7

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NK, natural killer.

  • An innate response can be initiated via the detection of pathogen-associated molecular patterns (PAMPs) in the vector genome or on vector particles8

  1. After the viral vector infects its target cell or an antigen-presenting cell, it uncoats and releases its genome, which can now be recognized by proteins such as toll-like receptors (TLRs), thus triggering the innate immune response8
  2. The capsid can also be degraded and presented via Class I or II MHCs, which activate CD8+ and CD4+ T cells, respectively8
  3. If the protein product of a transgene is completely absent in a patient prior to treatment, it can also be presented by Class I MHCs; this tags it for CD8+ T-cell destruction8,9
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Cytokines Implicated in Innate Immunity Include4,10:

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Figure reproduced from Figure 1 in Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
CCL, chemokine (C-C motif) ligand; CD, cluster of differentiation; IFN, interferon; IL, interleukin; Mda5, melanoma differentiation-associated protein 5; MHC, major histocompatibility complex; RANTES, regulated on activation, normally T-cell expressed, and secreted; RIG, retinoic-acid-inducible protein; TGF, transforming growth factor; TLR, toll-like receptor; TNF, tumor necrosis factor. 10

Adaptive Immune Response

Initiates 4-7 days post-infection4

The adaptive immune response is specific to the infecting pathogen and is triggered when the innate mechanisms are insufficient and a threshold antigen dose is reached.4,11 It requires days or weeks to develop and will leave an immunological memory for a faster response in the future4,12

Responses4,6

  • Pathogen-specific response
  • Immunological memory
  • Production of antibodies

Effectors4,7

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  • An adaptive immune response follows the innate immune response and involves activated T and B cells8

  1. Cell-mediated immunity – CD8+ T cells kill the infected cells via the release of perforin-containing and granzyme-containing cytotoxic granules8
  2. Humoral immunityCD4+ T cells activate plasma B cells, which in turn produce antibodies against the viral vector. Among these binding antibodies are a subset that can neutralize the effects of the gene therapy, often by binding to epitopes crucial for facilitating successful transduction of the target cells8,13,14
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  • As viral vectors used for gene therapies are based on human viruses, prior natural exposure may lead to the presence of pre-existing antibodies against the viral vector capsid15,16

Figure reproduced from Figure 1 in Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503. 
CD, cluster of differentiation.

References

  1. Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
  2. Bessis N, et al. Gene Ther 2004;11:S10–S17.
  3. Janeway CA. Proc Natl Acad Sci USA 2001;98(13):7461–7468.
  4. Janeway CA Jr, et al. Principles of innate and adaptive immunity. In: Immunobiology: The Immune System in Health and Disease. 5th edn. New York: Garland Science, 2001. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27090/. Accessed April 23, 2019.
  5. Biron CA. Chapter 4 – Innate immunity: recognizing and responding to foreign invaders – no training needed. In: Viral Pathogenesis: From Basics to Systems Biology. 3rd edn. Elsevier, 2016:41–55.
  6. Janeway CA Jr, et al. Induced innate responses to infection. In: Immunobiology: The Immune System in Health and Disease. 5th edn. New York: Garland Science, 2001. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27122/. Accessed April 23, 2019.
  7. Cruz CR, Bollard CM. Haematologica 2015;100(6):709–719.
  8. Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
  9. Al-Zaidy SA, Mendell JR. Pediatric Neurol 2019. doi: 10.1016/j.pediatrneurol.2019.06.007 [Epub ahead of print].
  10. Lacy P, Stow JL. Blood 2011;118(1):9–18.
  11. Janeway CA Jr, et al. The course of the adaptive response to infection. In: Immunobiology: The Immune System in Health and Disease. 5th edn. New York: Garland Science, 2001. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27125/. Accessed June 20, 2019.
  12. UpToDate®. An overview of the innate immune system. Available at: https://www.uptodate.com/contents/an-overview-of-the-innate-immune-system/print. Accessed June 21, 2019.
  13. U.S. FDA. The immunogenicity of therapeutic proteins- what you don’t know can hurt you and the patient. Available at: https://www.fda.gov/media/89071/download. Accessed June 25, 2019.
  14. Fitzpatrick Z, et al. Mol Ther Meth Clin Dev 2018;9:119–129.
  15. Kotterman MA, et al. Annu Rev Biomed Eng 2015;17:63–89.
  16. Boutin S, et al. Hum Gene Ther 2010;21(6):704–712.
  1. Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
  2. Bessis N, et al. Gene Ther 2004;11:S10–S17.
  3. Janeway CA. Proc Natl Acad Sci U S A 2001;98(13):7461–7468.
  4. Janeway CA Jr, et al. Principles of innate and adaptive immunity. In: Immunobiology: The Immune System in Health and Disease. 5th edn. New York: Garland Science, 2001. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27090/. Accessed April 23, 2019.
  5. Biron CA. Chapter 4 – Innate immunity: recognizing and responding to foreign invaders – no training needed. In: Viral Pathogenesis: From Basics to Systems Biology. 3rd edn. Elsevier, 2016:41–55.
  6. Janeway CA Jr, et al. Induced innate responses to infection. In: Immunobiology: The Immune System in Health and Disease. 5th edn. New York: Garland Science, 2001. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27122/. Accessed April 23, 2019.
  7. Cruz CR, Bollard CM. Haematologica 2015;100(6):709–719.
  8. Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
  9. Al-Zaidy SA, Mendell JR. Pediatric Neurol 2019. doi: 10.1016/j.pediatrneurol.2019.06.007 [Epub ahead of print].
  10. Lacy P, Stow JL. Blood 2011;118(1):9–18.
  11. Janeway CA Jr, et al. The course of the adaptive response to infection. In: Immunobiology: The Immune System in Health and Disease. 5th edn. New York: Garland Science, 2001. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27125/. Accessed June 20, 2019.
  12. UpToDate®. An overview of the innate immune system. Available at: https://www.uptodate.com/contents/an-overview-of-the-innate-immune-system/print. Accessed June 21, 2019.
  13. U.S. FDA. The immunogenicity of therapeutic proteins- what you don’t know can hurt you and the patient. Available at: https://www.fda.gov/media/89071/download. Accessed June 25, 2019.
  14. Fitzpatrick Z, et al. Mol Ther Meth Clin Dev 2018;9:119–129.
  15. Kotterman MA, et al. Annu Rev Biomed Eng 2015;17:63–89.
  16. Boutin S, et al. Hum Gene Ther 2010;21(6):704–712.