Transfusion medicine

Immunotherapy

Monoclonal antibody therapy


Editorial Board Members: Kyle Annen, D.O., Melissa R. George, D.O.
Mrigender Singh Virk, M.D.

Last author update: 13 April 2023
Last staff update: 19 April 2023

Copyright: 2022-2024, PathologyOutlines.com, Inc.

PubMed Search: Monoclonal antibody therapy

Mrigender Singh Virk, M.D.
Page views in 2024 to date: 163
Cite this page: Virk MS. Monoclonal antibody therapy. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedicinemonoclonalantibody.html. Accessed May 19th, 2024.
Definition / general
  • Monoclonal antibodies (mAbs) are novel therapeutics that are used in the management of hematologic malignancies, solid tumors, immune disorders, infections and several other conditions
  • These antibodies may occasionally interfere with serologic testing in the blood bank and require protocolized testing methods to ensure transfusion safety
Essential features
  • Monoclonal antibodies (mAbs) are used in the management of malignancies and immune disorders and may interfere with serologic testing in the blood bank
  • Anti-CD38 and anti-CD47 therapies are currently the most widely used mAbs that cause serology interference and blood banks should have protocols established to manage these patients
  • Anti-CD38 causes interference on antibody screens and requires reagent red cell treatment with diothiothreitol (DTT)
  • Anti-CD47 therapy can result in ABO discrepancies, positive direct antiglobulin test (DAT) and interference on antibody screens
Terminology
  • Naming conventions (Lancet 2022;399:24):
    • Prefixes are unique to distinguish each drug
    • Infixes designate the target (tu for tumor), antibody source (u for human) and modifications (zu for humanized)
    • Suffix was historically mab to designate monoclonal antibody; however, recent additions have been made to provide information about immunoglobulin structure
Pathophysiology
  • Mechanism of action (Oncogene 2003;22:9097):
    • mAbs generally target cell surface antigens or plasma soluble molecules such as proteins or drugs
    • Target and affinity for antigen is determined by variable region / complementarity determining region (CDR)
    • Fc (fragment crystallizable) portion supports the recruitment of other immune cells and complement factors to act on target
  • Monoclonal antibodies most relevant to transfusion medicine:
    • Anti-CD20 (rituximab) (Blood 2017;129:2971):
      • CD20 present on B cell lineage
      • Therapy results in downregulation of B cell receptor activity, decreased serum immunoglobulin production and increased apoptosis
      • Used to treat various lymphomas, leukemias and autoimmune diseases
      • Frequently used in conjunction with plasmapheresis for autoimmune neurologic disorders
      • May be considered in certain cases of autoimmune hemolytic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP) and Evans syndrome
    • Anti-CD38 (daratumumab and isatuximab) (Pathology 2021;53:427):
      • CD38 is overexpressed on multiple myeloma cells
      • Daratumamab causes indirect apoptosis through antibody dependent cellular cytoxicity (ADCC) via natural killer cells and complement dependent cytotoxicity (CDC)
      • Isatuximab induces direct cell apoptosis along with indirect apoptosis via ADCC and CDC
      • CD38 is expressed at low levels on red blood cells (RBCs)
      • See Laboratory for blood bank serologic testing issues related to CD38 expression on RBCs
    • Anti-CD47 (magrolimab - Hu5F9-G4) (Pathology 2021;53:427):
      • CD47 is widely expressed in the human body and acts as an antiphagocytic "do not eat me" marker on healthy cells
      • Therapy is primarily used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)
      • CD47 expression on RBCs can result in transient hemolysis upon initiation of therapy
      • See Laboratory for blood bank serologic testing issues related to CD47 expression on RBCs
    • Anti-C5 (eculizumab) (Transfus Med Rev 2019;33:256):
      • Inhibits the cleavage of C5 into C5a, an anaphylatoxin and proinflammatory molecule, and C5b, which forms the C5b-9 membrane attack complex that creates cytotoxic pores on cell surfaces
      • FDA approved for paroxysmal nocturnal hemoglobinuria (PNH), complement mediated thrombotic microangiopathy (referred to as atypical hemolytic uremic syndrome [aHUS]), refractory generalized myasthenia gravis and antiaquaporin 4+ neuromyelitis optica
      • Frequent off label use for other forms of thrombotic microangiopathy and other hematologic and autoimmune disorders
Clinical features
  • Adverse effects (Physiol Res 2016;65:S455):
    • Mild allergic infusion reactions are common and can be managed by pausing infusion, slowing infusion and with diphenhydramine
    • Acute hypersensitivity reactions and severe allergic reactions occur less frequently
    • Cytokine release syndrome (CRS) is a severe immune reaction that occurs in response to immunotherapy for certain cancers and leads to elevation in inflammatory cytokines
    • There is potential for infections and autoimmune reactions with the use of mAbs that reduce immune function
Laboratory
  • CD38 and CD47 expression on RBCs can cause serology interference and require protocols for testing and managing patients on therapies targeting these antigens (Pathology 2021;53:427)
  • Anti-CD38:
    • Therapy can result in interference with indirect antiglobulin testing (IAT)
    • Results in panreactive antibody screen and positive serologic crossmatch
    • Baseline ABO / Rh typing and antibody screen should be performed prior to initiating therapy
    • Baseline RBC phenotype / genotype to assess Rh, Kell, Jk, Fy and MNS antigen expression also recommended
    • Antibody screening should be performed with dithiothreitol (DTT) treatment of reagent RBCs to eliminate anti-CD38 binding and interference
      • Provide Kk compatible units due to DTT destruction of Kell antigens on reagent RBCs and inability to detect Kell alloantibodies
    • Soluble CD38 protein may also be used to neutralize anti-CD38 in patient plasma but it is not licensed for routine testing and difficult to acquire
    • Novel F(ab')2 fragments have been shown to directly block CD38 antigens on RBCs and overcome daratumumab interference but are not yet licensed or widely available (N Engl J Med 2018;379:90)
  • Anti-CD47:
    • Therapy can result in ABO discrepancies, positive DATs and positive antibody screens
    • Baseline ABO / Rh typing and antibody screen should be performed prior to initiating therapy
    • Baseline RBC phenotype / genotype to assess Rh, Kell, Jk, Fy and MNS antigen expression also recommended
    • Use type O RBCs if baseline ABO not determined or anomalous results encountered after initiating therapy
    • Adsorption studies with papain treated RBCs can be utilized for satisfactory antibody screening in cases with interference (Transfusion 2019;59:730)
    • Use of antihuman globulin (AHG) reagents that do not bind to IgG4 molecules has also demonstrated reduced interference as magrolimab is an IgG4 antibody (Transfusion 2019;59:730)
Case reports
  • 2 year old boy treated with daratumumab for post-hematopoietic stem cell transplantation refractory hemolytic anemia (Pediatr Blood Cancer 2020;67:e28010)
  • 19 year old woman treated with daratumumab in life threatening autoimmune hemolytic anemia following hematopoietic stem cell transplantation (Blood Adv 2018;2:2550)
  • 35 year old woman with posttransplant Evans syndrome treated with daratumumab (Br J Haematol 2019;187:e48)
  • 60 year old man treated with daratumumab for thrombocytopenia posttransplant (Blood Adv 2020;4:815)
  • 72 year old man treated with daratumumab for delayed red cell engraftment posttransplant (N Engl J Med 2018;379:1846)
Treatment
  • Monoclonal antibodies are usually administered parenterally but can also be administered intravenously, subcutaneously or intramuscularly, depending on the exact therapy and formulation
  • Use during plasmapheresis:
    • mAbs are present in the plasma and may be removed during plasmapheresis
    • Therapy plans that include apheresis should carefully consider dose timing to limit removal and allow for distribution to extravascular fluid compartments
Sample assessment & plan
  • Transfusion service serology report:
    • 70 year old man with multiple myeloma being treated with daratumumab (anti-CD38). Blood bank was alerted of the patient's medications and followed protocol for type and screen for patients on anti-CD38 therapy. Baseline testing on this patient prior to initiation of therapy demonstrated a blood type of A positive and a negative antibody screen. Repeat testing at this time confirms the A positive blood type. Antibody screening on the current sample was performed with DTT treatment of reagent red cells and also demonstrates a negative result.
    • Due to the use of DTT for antibody screening, we are unable to detect antibodies directed against antigens in the Kell blood group system and will provide the patient with K-k+ RBCs based on the patient's phenotype.
Board review style question #1
Your blood bank receives a type and screen sample for a 73 year old female patient that is new to your hospital and laboratory. The ABO / Rh typing is completed without issue and the patient demonstrates a blood type of O positive. The antibody screen is performed and shows that the patient's plasma causes 4+ agglutination with all 3 reagent red cells and the autocontrol is also positive. The blood bank technologist obtains additional clinical information and finds that this patient has multiple myeloma and is being treated with daratumumab. What serology method can be performed to eliminate the panreactivity on the antibody screen and identify underlying alloantibodies?

  1. Alloadsorption of patient's plasma
  2. Autoadsorption of patient's plasma
  3. Dithiothreitol treatment of patient's plasma
  4. Dithiothreitol treatment of reagent red cells
  5. Enzyme treatment of reagent red cells
Board review style answer #1
D. Dithiothreitol treatment of reagent red cells

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Reference: Monoclonal antibody therapy
Board review style question #2
Your blood bank receives a type and screen sample for a 75 year old male patient that is new to your hospital and laboratory. The ABO / Rh typing is completed without issue and the patient demonstrates a blood type of O positive. The antibody screen is performed and shows that the patient’s plasma causes 4+ agglutination with all 3 reagent red cells and the auto control is also positive. The blood bank technologist obtains additional clinical information and finds that this patient has multiple myeloma and is being treated with daratumumab. The blood bank technologist successfully uses DTT treatment to perform the antibody screen and finds that the screen is now negative. Which of the following blood products should be issued to the patient if an RBC is ordered?

  1. A positive irradiated RBCs because daratumumab reduces ABO antigen detection on forward typing
  2. O negative irradiated RBCs because daratumumab causes false positive RhD agglutination on forward type
  3. O positive irradiated RBCs with no additional special attributes
  4. O positive irradiated RBCs phenotypically matched for D, Cc and Ee antigens
  5. O positive irradiated RBCs phenotypically matched for K and k antigens
Board review style answer #2
E. O positive irradiated RBCs phenotypically matched for K and k antigens

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Reference: Monoclonal antibody therapy
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