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Capture: Seeing Beyond the Interference with Monoclonal Capture® : Seeing Beyond the Interference with Monoclonal Therapies Background For decades, patients diagnosed with cancer, leukemia, and many other diseases have been treated with chemotherapy. This systemic therapy relies upon cytotoxic agents introduced into the blood stream with the intent of interfering with the disease process, typically affecting cell division and leading to apoptosis. While the target of these drugs are the cells producing the disease, many times damage occurs to other, non-involved cells that divide rapidly such as hair follicle, digestive and bone marrow cells. More recently, monoclonal immunotherapy has become more clinically available. This therapy utilizes antibodies to stimulate the patient's immune system to attack specific cells. These antibodies bind to specific extracellular antigens and utilize elements of the immune system to remove the disease causing cells. Because this therapy allows for more specific targeting, there is typically less damage to normal cells. This therapy is quickly increasing in use due to both the antibodies' therapeutic success and numerous antibodies are in development. While traditional chemotherapies do not typically interfere with routine immunohematology testing, certain, specific monoclonal therapy agents have been documented to cause interference. The mechanism for interference depends upon each monoclonal therapy, the use of Immucor's Capture technology has been shown to reduce this interfence and allow for safe blood transfusion. Anti-CD38 Anti-CD38 treatments, including isatuximab and daratumumab (trade name Darzalex® ), are types of monoclonal therapy. These antibodies target CD38, which is found on the surface of many white blood cells, specifically lymphocytes. While having specific cellular functions, the presence of CD38 has been demonstrated as a prognostic marker for patients with chronic lymphocytic leukemia. Over expression of CD38 has been noted on multiple myeloma cells, leading to the use of these agents in treatment. The function of anti-CD38 drug therapy is to bind to the CD38 protein on the lymphocyte, initiate apoptosis, and target these cells for destruction and clearance bythe patient's immune system. CD38 is also expressed, at a low level, on the surface of red blood cells (RBCs). Therefore, when patient is treated with anti-CD38 therapy, their pre-transfusion testing can demonstrate unexpected positive reactivity in indirect antiglobulin (IAT) testing as the anti-CD38 binds with the testing RBCs. Laboratories have implemented a variety of mitigation strategies: using cord blood cells, dithiothreitol (DTT) or a neutralizing agent, while others have opted to perform molecular phenotyping on any patients known to have been on anti-CD38 therapy. Capture has been documented to be less subjected to this type of interference. The experience of Julie Staves, BSc (Hons), FIBMS of Oxford University Hospitals NHS Trust was published in ISBT's international journal of transfusion medicine, Vox Sanguinis, and presented at AABB 2018. The following chart documents the reactivity in gel column agglutination testing (CAT) compared to Capture solid phase testing. page 1 ® Capture : Seeing Beyond the Interference with Monoclonal Therapies Anti-CD47 Anti-CD47 is another type of monoclonal therapy increasing in utilization in clinical trials and is pending approval by the US Food and Drug administration (FDA) and European Medicines Agency (EMA). Hu5F9-G4 is currently the most common anti-CD47 therapy and is an IgG class 4 antibody. CD47 is involved in a range of cellular processes and serves as a marker of 'self' to the patient's immune system and is over expressed in many different types of tumor cells. Anti-CD47 conceals the CD47 protein; thus, making the cell more susceptible to macrophage phagocytosis. Because CD47 is universally expressed on all human cells, when patient serum or plasma containing this drug is utilized in pre-transfusion testing, unexpected positive reactivity can be observed in IAT and direct antiglobulin testing (DAT). In other words, the interference can be observed in blood type testing as well as antibody detection and identification. Laboratories are able to resolve anti-CD47 IAT interference by utilizing an anti-human globulin reagent developed from a clone that does not detect IgG class 4. The only reagents on the market are Immucor's Gamma-clone® Anti-IgG,-C3d; Polyspecific (Murine Monoclonal) & Gamma-clone® Anti-IgG (Murine Monoclonal). The anti- IgG murine monoclonal IgM antibodies are secreted by the heterohybridoma cell line 16H8. Testing during product development revealed lack of reactivity with IgG4 subclass antibodies, thus pure IgG4 subclass antibodies are not detected by these reagents. Dr. Connie Westhoff, director of genomics and immunohematology at New York Blood Center, described the use of these reagents in a recent article published in Transfusion "to remove the interferences [of anti-CD47] requires multiple RBC alloadsorportions and/or the use of monoclonal Gamma-clone Anti-IgG in the indirect antiglobulin testing". Additionally, the following table summarizes reactivity observed in gel CAT as well as tube testing with and without Gamma-clone as published in an AABB 2018 abstract by Advocate Lutheran General Hospital and ITxM. It is notable that the same clone utilized in the manufacture of this tube reagent, 16H8, is also utilized to develop Immucor's Capture-R® Ready Indicator Red Cells. Because Capture technology requires indicator cells to reveal the detection of antibodies, transfusion services can confidently automate pre-transfusion IAT testing even if the patient is known to have been on anti-CD47 therapy. Summary The use of anti-CD38, anti-CD47 (Hu5F9-G4), and other monoclonal therapies are likely to increase in frequency as more patients are successfully treated and more therapies are approved. Mitigation strategies for these therapies, while effective, are time consuming and inefficient. Implementation of Capture technology - through a manual Capture workstation or automated instrument - can reduce interference of the monoclonal therapies in pre-transfusion testing. page 2 Capture® : Seeing Beyond the Interference with Monoclonal Therapies References 1. CD38, CD38 molecule [Homo sapiens (human)] - Gene - NCBI. (2019, April 21). Retrieved from https://www.ncbi.nlm.nih.gov/ 2. Burgler S (2015). "Role of CD38 Expression in Diagnosis and Pathogenesis of Chronic Lymphocytic Leukemia and Its Potential as Therapeutic Target". Critical Reviews in Immunology. 35 (5): 417–32. 3. DeVooght KMK, Lozano M, Bueno JL, et al. VoxSanguinis International Forum on typing and matching strategies in patients on anti-CD38 monoclonal therapy: Summary. (2018, July). VoxSanguinis, 113(5), 492-498. 4. Staves, J. (Presenter). (2018, October 14). Antibody screening patients on monoclonal antibodies. Live performance at AABB Annual Meeting, Boston. 5. Stanford University Medical Center. Fibrosis reversed when 'don't eat me' signal blocked.(2017, April 17). Retrieved from https://medicalxpress.com. 6. Velliquette RW, Aeschlimann J, Kirkegaard J, et al. Monoclonal anti-CD47 interference in red cell and platelet testing. Transfusion, 2019, 59(2), 730-737. 7. Howard-Menk C, Crane JK, Doshi L, Papari M. HU5F9-G4 Monoclonal Anti-CD47 Therapy: A First Experience with Interference in Antibody Identification [Abstract]. Transfusion, 2019, 58(S2): 177A. page 3.
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