L 10

Antibody Preparations (Immunotherapy)

Instructor: Michael Volin, Ph.D.
Email: mvolin@Midwestern.edu

Objectives

  • Define Passive Immunization:

    • Passive immunization refers to the transfer of pre-formed antibodies (Ab) from one individual to another, providing immediate protection but lacking durability (as the recipient does not synthesize the antibodies). Different from active immunization in terms of time frame of effectiveness, mechanisms of action, and half-life of antibody preparations.

  • Compare Polyclonal and Monoclonal Antibodies:

    • Contrast characteristics, advantages, and disadvantages of polyclonal and monoclonal antibody preparations.

  • Define Immune Globulin Types:

    • Distinguish between immune globulin and specific immune globulin regarding preparation, clinical uses, efficacy, and contraindications.

  • Monoclonal Antibody Overview:

    • Define monoclonal antibodies, their production methods, mechanisms of action, and provide specific examples of their uses in clinical settings.

Passive Immunotherapy

  • Definition:

    • Results from the transfer of pre-formed immune components from one individual to another. It is relatively simple to transfer antibodies but more challenging for immune cells (as they require matching at MHC).

    • The term “passive” indicates that the recipient does not synthesize or metabolize the immune components, leading to immediate but temporary protection (effects do not last long).

  • Modes of Occurrence:

    • Can be obtained naturally (e.g., maternal antibodies) or artificially (e.g., from serum preparations).

Examples of Passive Immunotherapy Use

  1. Toxin Neutralization:

    • Example: Tetanus Immune Globulin (TIG).

  2. Disease Prevention Post-Exposure:

    • Example: Rabies immunoglobulin (IgG) following exposure to rabies virus.

  3. Immune Response Modulation:

    • Immune globulin preparations can either suppress or augment immune responses in conditions like autoimmune diseases.

Polyclonal Antibodies

  • Historical Context:

    • Historically referred to as “serum therapy,” which was the sole effective treatment for certain infectious diseases and toxemias prior to antibiotics. First used for measles prophylaxis around 1895, with initial applications for diphtheria.

  • Identification:

    • Immune globulins were first identified using serum electrophoresis, leading to the recognition that the γ-globulin fraction contained the majority of antibody activity, coining the term “immune globulin.”

  • Production:

    • Results from the immunization or recovery from an infection, leading to the activation of multiple B cells (plasma cells), yielding antibodies against multiple epitopes.

Characteristics of Polyclonal Antibody Preparations

  • Source and Concentration:

    • IgG concentrations can be increased through ethanol precipitation or ammonium sulfate concentration (up to 25-fold).

    • Common sources include sera and placentae.

    • Typically lyophilized (freeze-dried) for stability and later reconstituted in physiological saline.

Types of Immunoglobulin

  • Human Immune Globulin (HIG):

    • Derived from over 1,000 screened donors to ensure safety against bloodborne pathogens.

    • Provides high IgG levels suitable for therapeutic use.

  • Forms of Administration:

    • IMIG (intramuscular), SCIG (subcutaneous), IVIG (intravenous).

  • Specific Uses:

    • Measles post-exposure prophylaxis for immunocompromised individuals.

    • Management of hypogammaglobulinemia conditions, suppression of inflammatory/autoimmune reactions (such as Kawasaki’s disease, Guillain-Barre syndrome, and Myasthenia gravis).

Specific Human Immune Globulin (SHIG)

  • Derived from specific donors screened for high titers against certain pathogens.

  • Examples include:

    • RhoGAM (for hemolytic disease prophylaxis)

    • Varicella-zoster immune globulin (VariZIG)

    • Hepatitis B immune globulin (HBIG)

    • Human rabies immune globulin (HRIG)

    • Diphtheria immune globulin (DIG)

    • Cytomegalovirus immune globulin (CMV-IGIV)

    • Human tetanus immune globulin (HTIG)

    • COVID-19 convalescent plasma (emergency use authorization by FDA).

Other Forms of Polyclonal Antibody Preparations

  • Anti-sera:

    • These are raised in heterologous species (often horses) for specific toxins or venoms (snake, spider, scorpion), e.g., botulism toxin.

    • Complications include the potential for serum sickness.

Contraindications for Polyclonal Antibody Preparations

  • IgA Deficiency:

    • The most prevalent primary immune deficiency condition, which increases the risk of anaphylaxis from IgA responses or exposure.

Therapeutic Needs in Immunodeficiency

  • In a patient with agammaglobulinemia who presents with depleted antibody levels, the following preparations may be necessary:

    1. HBIG

    2. HTIG

    3. Immune globulin

    4. DIG

    5. CMVIG

Monoclonal Antisera: The Magic Bullet

  • Definition and Specificity:

    • Monoclonal antibodies (mAbs) arise from a clonal population derived from a single parental B cell. Each mAb is selective for a specific epitope, highlighting the advantage of specificity in targeting diseases.

  • Production of Monoclonal Antibodies:

    • Myeloma cells lack the enzyme HGPRT, making them unable to grow in HAT (Hypoxanthine-Aminopterin-Thymidine) medium unless they are fused with spleen cells that produce the desired antibodies. This entails cloning specific fused cells to isolate those producing the target-specific antibodies.

Challenges in Monoclonal Antibody Production

  • MAbs can be expensive, often derived from heterologous hosts (such as mice), necessitating humanization techniques to reduce immunogenicity while retaining therapeutic efficacy.

Advantages of Monoclonal Antibodies

  • Specificity and Consistency:

    • 100% of administered protein is the specific antibody for the designated antigen without lot-to-lot variations.

    • The prefix “mab” denotes the biological as a monoclonal preparation.

Nomenclature of Monoclonal Antibodies

  • Monoclonal antibodies are categorized with specific stems that indicate their source, usage, and targets.

  • Examples of Stems in Nomenclature:

    • -human (100% human)

    • -xi (chimeric, human/foreign)

    • -zu (humanized).

New Developments in Monoclonal Antibody Nomenclature (2022)

  • Examples include adintrevimab, an engineered antibody for COVID-19 prevention, granted emergency use authorization.

Overview of Approved Monoclonal Antibodies

  • FDA has approved numerous mAbs for therapeutic and diagnostic purposes, covering various conditions such as cancers and autoimmune diseases with classifications including murine, chimeric, humanized, and fully human formulations.

  • Biologics derived from older mAbs have the potential to be biosimilars, providing cost-effective alternatives to existing treatments.

Functions of Monoclonal Antibodies

  • Clinical Applications:

    • Prophylaxis for infectious diseases

    • Tumor targeting and therapeutic applications

    • Detection and treatment of cancers

    • Prevention of allograft rejection

    • Management of autoimmune diseases

    • Treatment for hypersensitivity reactions

    • Inhibition of leukocyte migration

    • Neutralization of cytokines

Prophylaxis Against Infectious Diseases

  • Example: Palivizumab (Synagis), a humanized anti-RSV F protein, indicates specific immunoglobulin attacks on the respiratory syncytial virus. Newer agents like Nirsevimab are noted for enhanced efficacy and longer lifespan in circulation.

Tumor Targeting and Treatment Mechanisms

  • Trastuzumab (Herceptin):

    • Targets the HER2 receptor leading to targeted cell depletion via opsonization, complement activation, and antibody-dependent cellular cytotoxicity (ADCC). Non-depleting mAbs act as receptor blockers without causing cellular destruction.

Cancer Detection and Treatment Examples

  • Ibritumomab Tiuxetan (Zevalin):

    • Murine mAb targeting CD20, evaluated for use in conjunction with radioisotope therapy for non-Hodgkin lymphoma detection and treatment.

  • Muromonab-CD3:

    • Utilized for prevention of transplant rejection via blockade of the CD3 receptor, effectively modulating T cell responses.

  • Omalizumab (Xolair):

    • Humanized antibody targeting IgE, offering therapeutic pathways for severe allergies and asthma management.

  • Natalizumab (Tysabri):

    • Humanized mAb used in the treatment of multiple sclerosis and Crohn's disease by preventing leukocyte migration to inflammatory sites in the brain and spinal cord.

  • Daclizumab (Zinbryta):

    • IL-2 receptor blocker used primarily to mitigate renal allograft rejection while containing T cell activation mechanisms.

  • Rituximab (Rituxan):

    • A chimeric mAb that targets CD20 molecules present on B cells, leading to cell depletion and therapeutic intervention for various autoimmune diseases.

  • Blinatumomab:

    • This bispecific mAb connects cytotoxic T cells to CD19+ cancer cells, specifically indicated for treating acute lymphoblastic leukemia.

Conclusion and Questions

  • The lecture concluded with an invitation for questions, emphasizing the critical importance of understanding the evolving landscape of antibody preparations in immunotherapy.