Engineering B cells to treat and study human disease

engineering-b-cells-to-treat-and-study-human-disease
Engineering B cells to treat and study human disease

References

  1. Ueda, N. et al. Immunotherapy perspectives in the new era of B-cell editing. Blood Adv. 5, 1770–1779 (2021).

    CAS  Google Scholar 

  2. Edelstein, J., Fritz, M. & Lai, S. K. Challenges and opportunities in gene editing of B cells. Biochem. Pharmacol. 206, 115285 (2022).

    CAS  Google Scholar 

  3. Jeske, A. M., Boucher, P., Curiel, D. & Voss, J. Vector strategies to actualize B cell-based gene therapies. J. Immunol. 207, 755–764 (2021).

    CAS  Google Scholar 

  4. Rogers, G. L. et al. Optimization of AAV6 transduction enhances site-specific genome editing of primary human lymphocytes. Mol. Ther. Methods Clin. Dev. 23, 198–209 (2021).

    CAS  Google Scholar 

  5. Page, A., Hubert, J., Fusil, F. & Cosset, F.-L. Exploiting B cell transfer for cancer therapy: engineered B cells to eradicate tumors. Int. J. Mol. Sci. 22, 9991 (2021).

    CAS  Google Scholar 

  6. Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).

    CAS  Google Scholar 

  7. Hibi, T. & Dosch, H. M. Limiting dilution analysis of the B cell compartment in human bone marrow. Eur. J. Immunol. 16, 139–145 (1986).

    CAS  Google Scholar 

  8. Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).

    CAS  Google Scholar 

  9. Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998).

    CAS  Google Scholar 

  10. Gorzelany, J. A. & de Souza, M. P. Protein replacement therapies for rare diseases: a breeze for regulatory approval? Sci. Transl. Med. 5, 178fs10 (2013).

    Google Scholar 

  11. Samelson-Jones, B. J. & George, L. A. Adeno-associated virus gene therapy for hemophilia. Annu. Rev. Med. 74, 231–247 (2023).

    CAS  Google Scholar 

  12. Srivastava, A. et al. Lentiviral gene therapy with CD34+ hematopoietic cells for hemophilia A. N. Engl. J. Med. 392, 450–457 (2025).

    CAS  Google Scholar 

  13. Tiede, A. Half-life extended factor VIII for the treatment of hemophilia A. J. Thromb. Haemost. 13, S176–S179 (2015).

    CAS  Google Scholar 

  14. Chen, H. H. et al. Enzyme replacement therapy for mucopolysaccharidoses; past, present, and future. J. Hum. Genet. 64, 1153–1171 (2019).

    Google Scholar 

  15. Chu, W. et al. Status and frontiers of Fabre disease. Orphanet J. Rare Dis. 20, 123 (2025).

    Google Scholar 

  16. Salabarria, S. M. et al. Advancements in AAV-mediated gene therapy for Pompe disease. J. Neuromuscul. Dis. 7, 15–31 (2020).

    CAS  Google Scholar 

  17. Placci, M., Giannotti, M. I. & Muro, S. Polymer-based drug delivery systems under investigation for enzyme replacement and other therapies of lysosomal storage disorders. Adv. Drug Deliv. Rev. 197, 114683 (2023).

    CAS  Google Scholar 

  18. Ozelo, M. C. et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N. Engl. J. Med. 386, 1013–1025 (2022).

    CAS  Google Scholar 

  19. Pipe, S. W. et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N. Engl. J. Med. 388, 706–718 (2023).

    CAS  Google Scholar 

  20. Mingozzi, F. & High, K. A. Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape. Annu. Rev. Virol. 4, 511–534 (2017).

    CAS  Google Scholar 

  21. Cunningham, S. C., Dane, A. P., Spinoulas, A. & Alexander, I. E. Gene delivery to the juvenile mouse liver using AAV2/8 vectors. Mol. Ther. 16, 1081–1088 (2008).

    CAS  Google Scholar 

  22. Hill, T. F. et al. Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing. Mol. Ther. https://doi.org/10.1016/j.ymthe.2024.06.004 (2024).

    Google Scholar 

  23. Luo, B. et al. Engineering of α-PD-1 antibody-expressing long-lived plasma cells by CRISPR/Cas9-mediated targeted gene integration. Cell Death Dis. 11, 973 (2020).

    CAS  Google Scholar 

  24. Moffett, H. F. et al. B cells engineered to express pathogen-specific antibodies protect against infection. Sci. Immunol. 4, eaax0644 (2019).

    CAS  Google Scholar 

  25. Silacci, P., Mottet, A., Steimle, V., Reith, W. & Mach, B. Developmental extinction of major histocompatibility complex class II gene expression in plasmocytes is mediated by silencing of the transactivator gene CIITA. J. Exp. Med. 180, 1329–1336 (1994).

    CAS  Google Scholar 

  26. Duan, M. et al. Understanding heterogeneity of human bone marrow plasma cell maturation and survival pathways by single-cell analyses. Cell Rep. 42, 112682 (2023).

    CAS  Google Scholar 

  27. Young, D. J. et al. In vivo tracking of ex-vivo-generated 89Zr-oxine-labeled plasma cells by PET in a non-human primate model. Mol. Ther. https://doi.org/10.1016/j.ymthe.2024.12.042 (2024).

    Google Scholar 

  28. Hung, K. L. et al. Engineering protein-secreting plasma cells by homology-directed repair in primary human B cells. Mol. Ther. 26, 456–467 (2018).

    CAS  Google Scholar 

  29. David, M. et al. Production of therapeutic levels of human FIX-R338L by engineered B cells using GMP-compatible medium. Mol. Ther. Methods Clin. Dev. 31, 101111 (2023).

    CAS  Google Scholar 

  30. Liu, H. et al. A precision gene engineered B cell medicine producing sustained levels of active factor IX for hemophilia B therapy. Preprint at bioRxiv https://doi.org/10.1101/2025.04.06.647090 (2025).

  31. Philippidis, A. Immusoft reports promising early data for lead candidate in MPS I. GEN—Genetic Engineering and Biotechnology News. www.genengnews.com/topics/drug-discovery/immusoft-reports-promising-early-data-for-lead-candidate-in-mps-i/ (2024).

  32. Pipe, S. W. et al. Become-9: a phase 1/2 dose escalation and expansion study of be-101 for the treatment of adults with moderately severe or severe hemophilia B. Blood 144, 2593.1 (2024).

    Google Scholar 

  33. Rastogi, I. et al. Role of B cells as antigen presenting cells. Front. Immunol. 13, 954936 (2022).

    CAS  Google Scholar 

  34. Okada, T. et al. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol. 3, e150 (2005).

    Google Scholar 

  35. Song, W. & Craft, J. T follicular helper cell heterogeneity: time, space, and function. Immunol. Rev. 288, 85–96 (2019).

    CAS  Google Scholar 

  36. Elsner, R. A. & Shlomchik, M. J. Germinal center and extrafollicular B cell responses in vaccination, immunity, and autoimmunity. Immunity 53, 1136–1150 (2020).

    CAS  Google Scholar 

  37. Hartweger, H. et al. HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells. J. Exp. Med. 216, 1301–1310 (2019).

    CAS  Google Scholar 

  38. Huang, D. et al. B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models. Proc. Natl Acad. Sci. USA 117, 22920–22931 (2020).

    CAS  Google Scholar 

  39. Huang, D. et al. Vaccine elicitation of HIV broadly neutralizing antibodies from engineered B cells. Nat. Commun. 11, 5850 (2020).

    CAS  Google Scholar 

  40. Nahmad, A. D. et al. Engineered B cells expressing an anti-HIV antibody enable memory retention, isotype switching and clonal expansion. Nat. Commun. 11, 5851 (2020).

    CAS  Google Scholar 

  41. Greiner, V. et al. CRISPR-mediated editing of the B cell receptor in primary human B cells. iScience 12, 369–378 (2019).

    CAS  Google Scholar 

  42. Voss, J. E. et al. Reprogramming the antigen specificity of B cells using genome-editing technologies. eLife 8, e42995 (2019).

    Google Scholar 

  43. Rogers, G. L. et al. Reprogramming human B cells with custom heavy-chain antibodies. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-024-01240-4 (2024).

    Google Scholar 

  44. Yin, Y. et al. In vivo affinity maturation of mouse B cells reprogrammed to express human antibodies. Nat. Biomed. Eng. 8, 361–379 (2024).

    CAS  Google Scholar 

  45. Wennhold, K. et al. Using antigen-specific B cells to combine antibody and T cell-based cancer immunotherapy. Cancer Immunol. Res. 5, 730–743 (2017).

    CAS  Google Scholar 

  46. Lee-Chang, C. et al. Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma. J. Exp. Med. 218, e20200913 (2021).

    CAS  Google Scholar 

  47. Wang, S. et al. B cell-based therapy produces antibodies that inhibit glioblastoma growth. J. Clin. Invest. 134, e177384 (2024).

    CAS  Google Scholar 

  48. Winkler, J. et al. Adoptive transfer of donor B lymphocytes: a phase 1/2a study for patients after allogeneic stem cell transplantation. Blood Adv. 8, 2373–2383 (2024).

    CAS  Google Scholar 

  49. Winkler, J. et al. GMP-grade generation of B-lymphocytes for adoptive immunotherapy in patients after allogeneic stem cell transplantation. Blood 120, 4352 (2012).

    Google Scholar 

  50. Winkler, J. et al. Adoptive transfer of purified donor-B-lymphocytes after allogeneic stem cell transplantation: results from a phase I/IIa clinical trial. Blood 128, 502 (2016).

    Google Scholar 

  51. Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 3, 944–950 (2002).

    CAS  Google Scholar 

  52. Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).

    CAS  Google Scholar 

  53. Parekh, V. V. et al. B cells activated by lipopolysaccharide, but not by anti-Ig and anti-CD40 antibody, induce anergy in CD8+ T cells: role of TGF-β 1. J. Immunol. 170, 5897–5911 (2003).

    CAS  Google Scholar 

  54. Knippenberg, S. et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. J. Neuroimmunol. 239, 80–86 (2011).

    CAS  Google Scholar 

  55. Blair, P. A. et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32, 129–140 (2010).

    CAS  Google Scholar 

  56. Flores-Borja, F. et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci. Transl. Med. 5, 173ra23 (2013).

    Google Scholar 

  57. Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).

    CAS  Google Scholar 

  58. Shankar, S. et al. Ex vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis. Nat. Commun. 13, 3121 (2022).

    CAS  Google Scholar 

  59. Lee, K. M. et al. Suppression of allograft rejection by regulatory B cells induced via TLR signaling. JCI Insight 7, e152213 (2022).

    Google Scholar 

  60. Bao, Y. et al. Ex vivo-generated human CD1c+ regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease. Mol. Ther. 32, 4372–4382 (2024).

    CAS  Google Scholar 

  61. Zambidis, E. T., Kurup, A. & Scott, D. W. Genetically transferred central and peripheral immune tolerance via retroviral-mediated expression of immunogenic epitopes in hematopoietic progenitors or peripheral B lymphocytes. Mol. Med. 3, 212–224 (1997).

    CAS  Google Scholar 

  62. El-Amine, M. et al. Mechanisms of tolerance induction by a gene-transferred peptide-IgG fusion protein expressed in B lineage cells. J. Immunol. 165, 5631–5636 (2000).

    CAS  Google Scholar 

  63. Melo, M. E. F. et al. Gene transfer of Ig-fusion proteins into B cells prevents and treats autoimmune diseases. J. Immunol. 168, 4788–4795 (2002).

    CAS  Google Scholar 

  64. Song, L. et al. Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-β? Gene Ther. 11, 1487–1496 (2004).

    CAS  Google Scholar 

  65. Lei, T. C. & Scott, D. W. Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins. Blood 105, 4865–4870 (2005).

    CAS  Google Scholar 

  66. Wang, X. et al. Immune tolerance induction to factor IX through B cell gene transfer: TLR9 signaling delineates between tolerogenic and immunogenic B cells. Mol. Ther. 22, 1139–1150 (2014).

    CAS  Google Scholar 

  67. Ahangarani, R. R. et al. In vivo induction of type 1-like regulatory T cells using genetically modified B cells confers long-term IL-10-dependent antigen-specific unresponsiveness. J. Immunol. 183, 8232–8243 (2009).

    Google Scholar 

  68. Calderón-Gómez, E. et al. Reprogrammed quiescent B cells provide an effective cellular therapy against chronic experimental autoimmune encephalomyelitis. Eur. J. Immunol. 41, 1696–1708 (2011).

    Google Scholar 

  69. Chen, D. et al. Novel engineered B lymphocytes targeting islet-specific T cells inhibit the development of type 1 diabetes in non-obese diabetic Scid mice. Front. Immunol. 14, 1227133 (2023).

    CAS  Google Scholar 

  70. Pitner, R. A. et al. Blunting specific T-dependent antibody responses with engineered ‘decoy’ B cells. Mol. Ther. 32, 3453–3469 (2024).

    CAS  Google Scholar 

  71. Luo, X. M. et al. Engineering human hematopoietic stem/progenitor cells to produce a broadly neutralizing anti-HIV antibody after in vitro maturation to human B lymphocytes. Blood 113, 1422–1431 (2009).

    CAS  Google Scholar 

  72. Cheng, R. Y.-H. et al. Ex vivo engineered human plasma cells exhibit robust protein secretion and long-term engraftment in vivo. Nat. Commun. 13, 6110 (2022).

    CAS  Google Scholar 

  73. He, W. et al. Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates. Immunity 56, 2408–2424.e6 (2023).

    CAS  Google Scholar 

  74. Serafini, M., Naldini, L. & Introna, M. Molecular evidence of inefficient transduction of proliferating human B lymphocytes by VSV-pseudotyped HIV-1-derived lentivectors. Virology 325, 413–424 (2004).

    CAS  Google Scholar 

  75. Janssens, W. et al. Efficiency of onco-retroviral and lentiviral gene transfer into primary mouse and human B-lymphocytes is pseudotype dependent. Hum. Gene Ther. 14, 263–276 (2003).

    CAS  Google Scholar 

  76. Frecha, C. et al. Efficient and stable transduction of resting B lymphocytes and primary chronic lymphocyte leukemia cells using measles virus gp displaying lentiviral vectors. Blood 114, 3173–3180 (2009).

    CAS  Google Scholar 

  77. Vamva, E. et al. A lentiviral vector B cell gene therapy platform for the delivery of the anti-HIV-1 eCD4-Ig-knob-in-hole-reversed immunoadhesin. Mol. Ther. Methods Clin. Dev. 28, 366–384 (2023).

    CAS  Google Scholar 

  78. Levy, C. et al. Baboon envelope pseudotyped lentiviral vectors efficiently transduce human B cells and allow active factor IX B cell secretion in vivo in NOD/SCIDγc−/− mice. J. Thromb. Haemost. 14, 2478–2492 (2016).

    CAS  Google Scholar 

  79. Bender, R. R. et al. Receptor-targeted Nipah virus glycoproteins improve cell-type selective gene delivery and reveal a preference for membrane-proximal cell attachment. PLoS Pathog. 12, e1005641 (2016).

    Google Scholar 

  80. Hamilton, J. R. et al. In vivo human T cell engineering with enveloped delivery vehicles. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-02085-z (2024).

    Google Scholar 

  81. Dobson, C. S. et al. Antigen identification and high-throughput interaction mapping by reprogramming viral entry. Nat. Methods 19, 449–460 (2022).

    CAS  Google Scholar 

  82. Yu, B. et al. Engineered cell entry links receptor biology with single-cell genomics. Cell 185, 4904–4920.e22 (2022).

    CAS  Google Scholar 

  83. Takano, K.-A. et al. Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo. Mol. Ther. 32, 1311–1327 (2024).

    CAS  Google Scholar 

  84. Ou, T. et al. Reprogramming of the heavy-chain CDR3 regions of a human antibody repertoire. Mol. Ther. 30, 184–197 (2022).

    CAS  Google Scholar 

  85. Johnson, M. J., Laoharawee, K., Lahr, W. S., Webber, B. R. & Moriarity, B. S. Engineering of primary human B cells with CRISPR/Cas9 targeted nuclease. Sci. Rep. 8, 12144 (2018).

    Google Scholar 

  86. Selvaraj, S. et al. High-efficiency transgene integration by homology-directed repair in human primary cells using DNA-PKcs inhibition. Nat. Biotechnol. 42, 731–744 (2024).

    CAS  Google Scholar 

  87. Sheridan, C. B cells as drug factories. Nat. Biotechnol. 42, 823–826 (2024).

    CAS  Google Scholar 

  88. Hackett, P. B. & Essner, J. Integration-site directed vector systems. US patent US7919583B2 (2005).

  89. Laoharawee, K. et al. Genome engineering of primary human B cells using CRISPR/Cas9. J. Vis. Exp. https://doi.org/10.3791/61855 (2020).

    Google Scholar 

  90. Giguère, S. et al. Antibody production relies on the tRNA inosine wobble modification to meet biased codon demand. Science 383, 205–211 (2024).

    Google Scholar 

  91. Christie, S. M., Fijen, C., & Rothenberg, E. V(D)J recombination: recent insights in formation of the recombinase complex and recruitment of DNA repair machinery. Front. Cell Dev. Biol. 10, 886718 (2022).

    Google Scholar 

  92. Nahmad, A. D. et al. In vivo engineered B cells secrete high titers of broadly neutralizing anti-HIV antibodies in mice. Nat. Biotechnol. 40, 1241–1249 (2022).

    CAS  Google Scholar 

  93. Russell, D. M. et al. Peripheral deletion of self-reactive B cells. Nature 354, 308–311 (1991).

    CAS  Google Scholar 

  94. Abbott, R. K. et al. Precursor frequency and affinity determine B cell competitive fitness in germinal centers, tested with germline-targeting HIV vaccine immunogens. Immunity 48, 133–146.e6 (2018).

    CAS  Google Scholar 

  95. Dosenovic, P. et al. Anti–HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity. Proc. Natl Acad. Sci. USA 115, 4743–4748 (2018).

    CAS  Google Scholar 

  96. Tokatlian, T. et al. Enhancing humoral responses against HIV envelope trimers via nanoparticle delivery with stabilized synthetic liposomes. Sci. Rep. 8, 16527 (2018).

    Google Scholar 

  97. Wagar, L. E. et al. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27, 125–135 (2021).

    CAS  Google Scholar 

  98. Pan, A. et al. In vivo affinity maturation of the CD4 domains of an HIV-1-entry inhibitor. Nat. Biomed. Eng. 8, 1715–1729 (2024).

    CAS  Google Scholar 

  99. Buerstedde, J.-M., Alinikula, J., Arakawa, H., McDonald, J. J. & Schatz, D. G. Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. PLoS Biol. 12, e1001831 (2014).

    Google Scholar 

  100. O’Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–98 (2004).

    Google Scholar 

  101. Wallweber, H. J. A., Compaan, D. M., Starovasnik, M. A. & Hymowitz, S. G. The crystal structure of a proliferation-inducing ligand. April. J. Mol. Biol. 343, 283–290 (2004).

    CAS  Google Scholar 

  102. Lapidot, T. Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. Ann. N. Y. Acad. Sci. 938, 83–95 (2001).

    CAS  Google Scholar 

  103. Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).

    CAS  Google Scholar 

  104. Chatterjee, S., Behnam Azad, B. & Nimmagadda, S. The intricate role of CXCR4 in cancer. Adv. Cancer Res. 124, 31–82 (2014).

    CAS  Google Scholar 

  105. Vonderheide, R. H., Tedder, T. F., Springer, T. A. & Staunton, D. E. Residues within a conserved amino acid motif of domains 1 and 4 of VCAM-1 are required for binding to VLA-4. J. Cell Biol. 125, 215–222 (1994).

    CAS  Google Scholar 

  106. Newham, P. et al. Α4 integrin binding interfaces on VCAM-1 and MAdCAM-1. J. Biol. Chem. 272, 19429–19440 (1997).

    CAS  Google Scholar 

  107. Benet, Z., Jing, Z. & Fooksman, D. R. Plasma cell dynamics in the bone marrow niche. Cell Rep. 34, 108733 (2021).

    CAS  Google Scholar 

  108. Nguyen, D. C. et al. Author correction: factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion. Nat. Commun. 10, 372 (2019).

    Google Scholar 

  109. Roldán, E., García-Pardo, A. & Brieva, J. A. VLA-4-fibronectin interaction is required for the terminal differentiation of human bone marrow cells capable of spontaneous and high rate immunoglobulin secretion. J. Exp. Med. 175, 1739–1747 (1992).

    Google Scholar 

  110. Fiorillo, M. T., Cabibbo, A., Iacopetti, P., Fattori, E. & Ciliberto, G. Analysis of human/mouse interleukin-6 hybrid proteins: both amino and carboxy termini of human interleukin-6 are required for in vitro receptor binding. Eur. J. Immunol. 22, 2609–2615 (1992).

    CAS  Google Scholar 

  111. Neuber, T. et al. Characterization and screening of IgG binding to the neonatal Fc receptor. MAbs 6, 928–942 (2014).

    Google Scholar 

  112. Ober, R. J., Radu, C. G., Ghetie, V. & Ward, E. S. Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies. Int. Immunol. 13, 1551–1559 (2001).

    CAS  Google Scholar 

  113. Andersen, J. T., Daba, M. B., Berntzen, G., Michaelsen, T. E. & Sandlie, I. Cross-species binding analyses of mouse and human neonatal Fc receptor show dramatic differences in immunoglobulin G and albumin binding. J. Biol. Chem. 285, 4826–4836 (2010).

    Google Scholar 

  114. Li, F. et al. Mouse strains influence clearance and efficacy of antibody and antibody-drug conjugate via Fc-FcγR interaction. Mol. Cancer Ther. 18, 780–787 (2019).

    CAS  Google Scholar 

  115. Oldham, R. J. et al. FcγRII (CD32) modulates antibody clearance in NOD SCID mice leading to impaired antibody-mediated tumor cell deletion. J. Immunother. Cancer 8, e000619 (2020).

    Google Scholar 

  116. Yu, H. et al. A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood 129, 959–969 (2017).

    CAS  Google Scholar 

  117. Li, Y. et al. A human immune system mouse model with robust lymph node development. Nat. Methods 15, 623–630 (2018).

    CAS  Google Scholar 

  118. Chupp, D. P. et al. A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses. Nat. Immunol. https://doi.org/10.1038/s41590-024-01880-3 (2024).

    Google Scholar 

  119. Sun, K. & Liao, M. Z. Clinical pharmacology considerations on recombinant adeno-associated virus-based gene therapy. J. Clin. Pharmacol. 62, S79–S94 (2022).

    CAS  Google Scholar 

  120. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    CAS  Google Scholar 

  121. Tsuchida, C. A. et al. Mitigation of chromosome loss in clinical CRISPR–Cas9-engineered T cells. Cell 186, 4567–4582.e20 (2023).

    CAS  Google Scholar 

  122. Lazar, N. H. et al. High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR-Cas9 editing. Nat. Genet. 56, 1482–1493 (2024).

    CAS  Google Scholar 

  123. Nahmad, A. D. et al. Frequent aneuploidy in primary human T cells after CRISPR–Cas9 cleavage. Nat. Biotechnol. 40, 1807–1813 (2022).

    CAS  Google Scholar 

  124. Zhang, T.-T. et al. BCR signaling is required for posttransplant lymphoproliferative disease in immunodeficient mice receiving human B cells. Sci. Transl. Med. 16, eadh8846 (2024).

    CAS  Google Scholar 

  125. Stockfelt, M., Teng, Y. K. O. & Vital, E. M. Opportunities and limitations of B cell depletion approaches in SLE. Nat. Rev. Rheumatol. 21, 111–126 (2025).

    Google Scholar 

  126. Gargett, T. & Brown, M. P. The inducible caspase-9 suicide gene system as a “safety switch†to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front. Pharmacol. 5, 235 (2014).

    Google Scholar 

  127. Dunkelberger, J. R. & Song, W.-C. Complement and its role in innate and adaptive immune responses. Cell Res. 20, 34–50 (2010).

    CAS  Google Scholar 

  128. Ma, A. D. & Carrizosa, D. Acquired factor VIII inhibitors: pathophysiology and treatment. Hematol. Am. Soc. Hematol. Educ. Program 2006, 432–437 (2006).

    Google Scholar 

  129. Jawa, V. et al. T-cell dependent immunogenicity of protein therapeutics pre-clinical assessment and mitigation-updated consensus and review 2020. Front. Immunol. 11, 1301 (2020).

    CAS  Google Scholar 

  130. Sabatino, D. E. et al. Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol. Ther. 19, 442–449 (2011).

    CAS  Google Scholar 

  131. Annoni, A. et al. Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice. EMBO Mol. Med. 5, 1684–1697 (2013).

    CAS  Google Scholar 

  132. Chand, D. et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J. Hepatol. 74, 560–566 (2021).

    CAS  Google Scholar 

  133. Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 12, 342–347 (2006).

    CAS  Google Scholar 

  134. Gallo-Penn, A. M. et al. Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs. Blood 97, 107–113 (2001).

    CAS  Google Scholar 

  135. Grauwet, K. et al. Stealth transgenes enable CAR-T cells to evade host immune responses. J. Immunother. Cancer 12, e008417 (2024).

    Google Scholar 

  136. Wang, B. et al. Generation of hypoimmunogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells. Nat. Biomed. Eng. 5, 429–440 (2021).

    CAS  Google Scholar 

  137. Hu, X. et al. Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-01784-x (2023).

    Google Scholar 

  138. Gupta, P., Alheib, O. & Shin, J.-W. Towards single cell encapsulation for precision biology and medicine. Adv. Drug Deliv. Rev. 201, 115010 (2023).

    CAS  Google Scholar 

  139. Kershaw, M. H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).

    CAS  Google Scholar 

  140. Hartweger, H. et al. Gene editing of primary rhesus macaque B cells. J. Vis. Exp. https://doi.org/10.3791/64858 (2023).

    Google Scholar 

  141. Vamva, E. et al. An optimized measles virus glycoprotein-pseudotyped lentiviral vector production system to promote efficient transduction of human primary B cells. STAR Protoc. 3, 101228 (2022).

    CAS  Google Scholar 

  142. Yu-Hong Cheng, R. et al. Generation, expansion, gene delivery, and single-cell profiling in rhesus macaque plasma B cells. Cell Rep. Methods 4, 100878 (2024).

    CAS  Google Scholar 

  143. Ishikawa, M. et al. Bone marrow plasma cells require P2RX4 to sense extracellular ATP. Nature 626, 1102–1107 (2024).

    CAS  Google Scholar 

  144. Van Dam, M. et al. Structure–function analysis of interleukin-6 utilizing human/murine chimeric molecules. Involvement of two separate domains in receptor binding. J. Biol. Chem. 268, 15285–15290 (1993).

    Google Scholar 

Download references