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Translating B cell immunology to the treatment of antibody-mediated allograft rejection

Nature Reviews Nephrology volume 20, pages 218–232 (2024)Cite this article

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Abstract

Antibody-mediated rejection (AMR), including chronic AMR (cAMR), causes ~50% of kidney allograft losses each year. Despite attempts to develop well-tolerated and effective therapeutics for the management of AMR, to date, none has obtained FDA approval, thereby highlighting an urgent unmet medical need. Discoveries over the past decade from basic, translational and clinical studies of transplant recipients have provided a foundation for developing novel therapeutic approaches to preventing and treating AMR and cAMR. These interventions are aimed at reducing donor-specific antibody levels, decreasing graft injury and fibrosis, and preserving kidney function. Innovative approaches emerging from basic science findings include targeting interactions between alloreactive T cells and B cells, and depleting alloreactive memory B cells, as well as donor-specific antibody-producing plasmablasts and plasma cells. Therapies aimed at reducing the cytotoxic antibody effector functions mediated by natural killer cells and the complement system, and their associated pro-inflammatory cytokines, are also undergoing evaluation. The complexity of the pathogenesis of AMR and cAMR suggest that multiple approaches will probably be required to treat these disease processes effectively. Definitive answers await results from large, double-blind, multicentre, randomized controlled clinical trials.

Key points

  • Understanding the expression pattern of surface antigens — including CD19, CD20 and CD38 — on B cell subsets can guide strategies for using monoclonal antibodies to deplete relevant effector B cell subsets.

  • Enhanced understanding of the pleiotropic effects of IL-6–IL-6 receptor signalling in antibody-mediated rejection has led to early trials targeting IL-6R (tocilizumab) or IL-6 (clazakizumab) as potential effective therapies.

  • Plasma cell depletion strategies used in the treatment of multiple myeloma, including proteosome inhibition and an anti-CD38 monoclonal antibody (daratumumab)-mediated depletion of plasma cells, are being tested in kidney transplant recipients with chronic antibody-mediated rejection.

  • New approaches to targeting antibody effector functions with C1 esterase inhibitor (blocks classical and mannose-binding lectin complement pathways), eculizumab (inhibits terminal complement and membrane-attack complex (MAC) formation), imlifidase (cleaves antibody Fc region) and neonatal Fc receptor monoclonal antibodies (prevent antibody recycling and shorten antibody half-lives) show promise for preventing or treating antibody-mediated rejection.

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Fig. 1: Progression of B cell development in the bone marrow and peripheral circulation.
Fig. 2: Alloimmune B cell differentiation and therapeutic targets.
Fig. 3: Therapeutic targeting of antibody and complement-mediated cytotoxicity in transplantation.

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Acknowledgements

The authors acknowledge and thank all the kidney allograft recipients and their families who have participated in clinical trials aimed at eliminating antibody rejection and improving outcomes. We also want to acknowledge the team members of the Kidney Transplant Program, Transplant Immunotherapy Program, Transplant Immunology Laboratory, and HLA Laboratory at Cedars-Sinai Medical Center for their commitment to improving lives through transplantation. P.S.H. is supported by R01AI141434 and M.C.H. is supported by T32 AI078892.

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Authors and Affiliations

  1. Comprehensive Transplant Center, Department of Medicine, Division of Nephrology Cedars-Sinai Medical Center Los Angeles, Los Angeles, CA, USA

    Peter S. Heeger & Stanley Jordan

  2. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, Mount Sinai, NY, USA

    Maria Carrera Haro

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  1. Peter S. Heeger
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  2. Maria Carrera Haro
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Contributions

All authors researched data and wrote the article. S.J. and P.S.H. made substantial contributions to discussions of the content, and reviewed or edited the manuscript before submission.

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Correspondence to Stanley Jordan.

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Competing interests

S.J. has grants and consulting fees from Hansa Biopharma, CSL-Behring, Regeneron, Sana Biotechnology and Argenx. P.S.H. and M.C.H. declare no competing interests.

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Nature Reviews Nephrology thanks G. Böhmig, T. Jouve and J. Kwun for their contribution to the peer review of this work.

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Glossary

Antibody recycling

A cellular process in which antibodies bound to FcRn are endocytosed and then released back into the circulation without undergoing degradation.

Idiotypic

An idiotype is the distinctive amino acid sequence within the variable region that makes any immunoglobulin (or T cell receptor) unique. Anti-idiotypic antibodies are specifically reactive to these idiotypes.

Somatic hypermutation

A process within B cells in which point mutations accumulate in the V regions of antibody light and heavy chains to enhance antibody affinity for a given antigen.

Transitional B cells

Immature B cells that have recently left the bone marrow.

Type 1 anti-CD20

Examples include rituximab and ofatumumab. These antibodies cause redistribution of CD20 into lipid rafts within the plasma membrane, which can enhance their effector mechanisms, but are more susceptible to internalization and proteolytic degradation than type 2 anti-CD20 monoclonal antibodies.

Type 2 anti-CD20

Obinutuzumab. Compared with the type 1 counterparts, this antibody shows enhanced binding to FcγRIII and enhanced antibody-dependent cytotoxicity function, as well as reduced internalization, which might enhance its efficacy.

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Heeger, P.S., Haro, M.C. & Jordan, S. Translating B cell immunology to the treatment of antibody-mediated allograft rejection. Nat Rev Nephrol 20, 218–232 (2024). https://doi.org/10.1038/s41581-023-00791-0

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