Antibody Therapeutics as Interfering Agents in Flow Cytometry Crossmatch for Organ Transplantation

Donor–recipient matching is a highly individualized and complex component of solid organ transplantation. Flowcytometry crossmatching (FC-XM) is an integral step in the matching process that is used to detect pre-formed deleterious anti-donor immunoglobulin. Despite high sensitivity in detecting cell-bound immunoglobulin, FC-XM is not able to determine the source or function of immunoglobulins detected. Monoclonal antibody therapeutic agents used in a clinic can interfere with the interpretation of FC-XM. We combined data from the prospectively maintained Antibody Society database and Human Protein Atlas with a comprehensive literature review of PubMed to summarize known FC-XM-interfering antibody therapeutics and identify potential interferers. We identified eight unique FC-XM-interfering antibody therapeutics. Rituximab (anti-CD20) was the most-cited agent. Daratumuab (anti-CD38) was the newest reported agent. We identified 43 unreported antibody therapeutics that may interfere with FC-XM. As antibody therapeutic agents become more common, identifying and mitigating FC-XM interference will likely become an increased focus for transplant centers.

[1]  M. Cusick,et al.  Daratumumab Interferes with Allogeneic Crossmatch Impacting Immunological Assessment in Solid Organ Transplantation , 2022, Journal of Clinical Medicine.

[2]  Xuping Xie,et al.  The arrival of SARS-CoV-2–neutralizing antibodies in a currently available commercial immunoglobulin , 2022, Journal of Allergy and Clinical Immunology.

[3]  S. Jordan,et al.  Obinutuzumab in Kidney Transplantation: Effect on B-cell Counts and Crossmatch Tests. , 2021, Transplantation.

[4]  E. Oh,et al.  Causes of Positive Pretransplant Crossmatches in the Absence of Donor-Specific Anti-Human Leukocyte Antigen Antibodies: A Single-Center Experience , 2021, Annals of laboratory medicine.

[5]  J. Schmitz,et al.  Abrogating biologics interference in flow cytometric crossmatching. , 2021, Human immunology.

[6]  A. Nambiar,et al.  Impact of new myeloma agents on the transfusion laboratory. , 2021, Pathology.

[7]  L. Rostaing,et al.  Obinutuzumab in Kidney Transplantation: Effect on B-cell Counts and Crossmatch Tests , 2021, Transplantation.

[8]  D. Daniel,et al.  Impact of rituximab on the T-cell flow cytometric crossmatch. , 2020, Transplant immunology.

[9]  M. Gandhi,et al.  Daratumumab interference in flow cytometric anti‐granulocyte antibody testing can be overcome using non‐human blocking antibodies , 2020, Vox sanguinis.

[10]  M. Stegall,et al.  Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use. , 2019, Journal of the American Society of Nephrology : JASN.

[11]  N. Guillaume Improved flow cytometry crossmatching in kidney transplantation , 2018, HLA.

[12]  Robert A Bray,et al.  (F)Utility of the physical crossmatch for living donor evaluations in the age of the virtual crossmatch. , 2018, Human immunology.

[13]  Bertram L Kasiske,et al.  An economic assessment of contemporary kidney transplant practice , 2018, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  M. Althaf,et al.  Human leukocyte antigen typing and crossmatch: A comprehensive review , 2017, World journal of transplantation.

[15]  A. Wikström,et al.  Pronase independent flow cytometry crossmatching of rituximab treated patients. , 2017, Human immunology.

[16]  P. Moreau,et al.  Daratumumab for the treatment of multiple myeloma , 2017, Expert opinion on biological therapy.

[17]  P. Parren,et al.  When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy , 2015, Transfusion.

[18]  J. Laubach,et al.  Resolving the daratumumab interference with blood compatibility testing , 2015, Transfusion.

[19]  L. Rostaing,et al.  Interference of therapeutic antibodies used in desensitization protocols on lymphocytotoxicity crossmatch results. , 2015, Transplant immunology.

[20]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[21]  B. Ostrov,et al.  The interference of monoclonal antibodies with laboratory diagnosis: clinical and diagnostic implications , 2013, Immunological investigations.

[22]  P. Nickerson,et al.  Posttransplant monitoring of de novo human leukocyte antigen donor-specific antibodies in kidney transplantation , 2013, Current opinion in organ transplantation.

[23]  C. Haisch,et al.  Incidence and Impact of De Novo Donor-Specific Alloantibody in Primary Renal Allografts , 2013, Transplantation.

[24]  A. Webster,et al.  Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation , 2013, Transplantation.

[25]  P. Terasaki A personal perspective: 100-year history of the humoral theory of transplantation. , 2012, Transplantation.

[26]  J. Kanellis,et al.  Understanding crossmatch testing in organ transplantation: A case‐based guide for the general nephrologist , 2011, Nephrology.

[27]  R. Bray,et al.  Cytotoxicity and antibody binding by flow cytometry: A single assay to simultaneously assess two parameters , 2008, Cytometry. Part B, Clinical cytometry.

[28]  M. Pescovitz,et al.  New crossmatch technique eliminates interference by humanized and chimeric monoclonal antibodies. , 2005, Transplantation proceedings.

[29]  M. Pescovitz,et al.  Pronase treatment facilitates alloantibody flow cytometric and cytotoxic crossmatching in the presence of rituximab. , 2004, Human immunology.

[30]  P. Terasaki,et al.  Predicting Kidney Graft Failure by HLA Antibodies: a Prospective Trial , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[31]  S. Ballas,et al.  False‐positive HLA antibody screen associated with Campath administration , 2001, Transfusion.

[32]  F. Schuber,et al.  Probing ligand-induced conformational changes of human CD38. , 2000, European journal of biochemistry.

[33]  D. Reichenbach,et al.  The clinical significance of flow cytometry crossmatching in heart transplantation. , 1998, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[34]  E. Zocchi,et al.  Structural role of disulfide bridges in the cyclic ADP‐ribose related bifunctional ectoenzyme CD38 , 1995, FEBS letters.

[35]  P. Terasaki,et al.  Significance of the positive crossmatch test in kidney transplantation. , 1969, The New England journal of medicine.

[36]  H. Gebel,et al.  Of Cells and Microparticles: Assets and Liabilities of HLA Antibody Detection. , 2018, Transplantation.

[37]  David M. Conrad,et al.  Rapid optimized flow cytometric crossmatch (FCXM) assays: The Halifax and Halifaster protocols. , 2018, Human immunology.

[38]  B. Rutkowski,et al.  Modified flow cytometry crossmatch detecting alloantibody-related cytotoxicity as a way to distinguish lytic antibodies from harmless in allosensitised kidney recipients. , 2013, Transplantation proceedings.

[39]  A. Ingsathit,et al.  Cytotoxic flow cytometric crossmatch in renal transplantation: a single assay to simultaneously detect antibody binding and cytotoxicity. , 2012, Transplantation proceedings.

[40]  U. Ott,et al.  General insufficiency of the classical CDC-based crossmatch to detect donor-specific anti-HLA antibodies leading to invalid results under recipients' medical treatment or underlying diseases. , 2012, Histology and histopathology.

[41]  Mark Walport,et al.  The major histocompatibility complex and its functions , 2001 .

[42]  R. Bray Flow cytometry crossmatching for solid organ transplantation. , 1994, Methods in cell biology.

[43]  H. Perkins,et al.  Flow cytometry analysis: A high technology cross-match technique facilitating transplantation , 1983 .