Immunogenicity of Gene Therapies
Innate Immune Response
Initiates within hours post-infection5
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
- 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
- The capsid can also be degraded and presented via Class I or II MHCs, which activate CD8+ and CD4+ T cells, respectively8
- 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
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
An adaptive immune response follows the innate immune response and involves activated T and B cells8
- Cell-mediated immunity – CD8+ T cells kill the infected cells via the release of perforin-containing and granzyme-containing cytotoxic granules8
- Humoral immunity – CD4+ 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
Figure reproduced from Figure 1 in Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
CD, cluster of differentiation.
References
- Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
- Bessis N, et al. Gene Ther 2004;11:S10–S17.
- Janeway CA. Proc Natl Acad Sci USA 2001;98(13):7461–7468.
- 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.
- 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.
- 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.
- Cruz CR, Bollard CM. Haematologica 2015;100(6):709–719.
- Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
- Al-Zaidy SA, Mendell JR. Pediatric Neurol 2019. doi: 10.1016/j.pediatrneurol.2019.06.007 [Epub ahead of print].
- Lacy P, Stow JL. Blood 2011;118(1):9–18.
- 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.
- 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.
- 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.
- Fitzpatrick Z, et al. Mol Ther Meth Clin Dev 2018;9:119–129.
- Kotterman MA, et al. Annu Rev Biomed Eng 2015;17:63–89.
- Boutin S, et al. Hum Gene Ther 2010;21(6):704–712.
- Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
- Bessis N, et al. Gene Ther 2004;11:S10–S17.
- Janeway CA. Proc Natl Acad Sci U S A 2001;98(13):7461–7468.
- 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.
- 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.
- 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.
- Cruz CR, Bollard CM. Haematologica 2015;100(6):709–719.
- Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
- Al-Zaidy SA, Mendell JR. Pediatric Neurol 2019. doi: 10.1016/j.pediatrneurol.2019.06.007 [Epub ahead of print].
- Lacy P, Stow JL. Blood 2011;118(1):9–18.
- 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.
- 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.
- 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.
- Fitzpatrick Z, et al. Mol Ther Meth Clin Dev 2018;9:119–129.
- Kotterman MA, et al. Annu Rev Biomed Eng 2015;17:63–89.
- Boutin S, et al. Hum Gene Ther 2010;21(6):704–712.