Therapeutic Antibodies: Uses and Mechanisms

• Antibodies can be therapeutic agents as drugs and drug carriers.

Antibodies as Drugs: Uses

• Neutralize and eliminate pathogenic or toxic molecules.
• Eliminate target cells.

Neutralizing Pathogenic or Toxic Molecules

• Antibodies bind antigen molecules, forming antigen-antibody complexes, cleared from the blood through the reticuloendothelial system or kidneys.
• This process can eliminate pathogens or toxic substances from the blood or tissues selectively.
• Using intact antibodies as neutralizing agents can cause type III hypersensitivity (serum sickness).

Use of Antibodies

• Antibodies in antiserum form are used to save lives from infections or poisoning.
• Rabbit antisera against snake venoms are antidotes for poisonous snake bites.
• Anti-diphtheria, anti-tetanus, and toxin antisera are used for diphtheria treatment.
• Antibodies can treat drug toxicity, for example digoxin poisoning.

Antibodies for Eliminating Target Cells

• Antibodies, not inherently cytotoxic, don't directly cause cell death upon binding to target cell membrane antigens.
• Antibody binding can lead to cell death or growth inhibition through four possible mechanisms:
• Regulatory growth control
• Reticuloendothelial clearance
• Complement-mediated cytotoxicity (CMC)
• Antibody-dependent cell-mediated cytotoxicity (ADCC)

Regulatory Growth Control

• Antibodies can bind to growth factors or their receptors, interfering with growth factor accessibility to target cells.
• Antibody binding on surface markers can promote tumor cell differentiation to normal cells, useful in differentiation therapy.

Reticuloendothelial Clearance

• Antibody-coated target cells are engulfed by phagocytes, mainly macrophages, in the reticuloendothelial system (RES) via phagocytosis.
• Antibodies facilitate phagocytosis by opsonizing target cells for Fc or C3b receptors on phagocytes.

Complement-Mediated Cytotoxicity (CMC)

• IgG or IgM antibodies, bound to target cell surface antigens, trigger the classic complement pathway.
• Complement activation leads to cytotoxicity by forming the membrane attack complex (MAC).

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

• Antibody-bound target cells are recognized and killed by killer cells or macrophages via Fc-receptors.
• The killing process involves cell-cell contact and release of cytotoxic substances from effector to target cells.
• ADCC represents major function of macrophages or killer cells in killing tumor cells too large for phagocytosis by the RES.

Regulatory Growth Control - Schematic Summary (A)

• Antibodies against growth factors or receptors, like autocrine growth factors in tumor cells, can inhibit cell proliferation.
• Antiidiotypic antibodies against B-cell surface immunoglobulins may induce B-cell and plasma cell differentiation.

Reticuloendothelial Clearance - Schematic Summary (B)

• Antibody binding enhances phagocytosis by macrophages via opsonization mediated by Fc receptors.

Complement-Mediated Cytotoxicity - Schematic Summary (C)

• Complement fixation causes lysis of antibody-bound target cells.

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) - Schematic Summary (D)

• Binding of antibody causes death of target cells such as K cells that bind via a Fc receptor.

Commercial Antibodies as Drugs: Types

• Human immunoglobulins: Sourced from pooled human plasma of donors or hyperimmunized donors, used for treating immunodeficiency syndrome and preventing infection in chronic lymphocytic leukemia. Examples include Gammagard®, Sandoglobulin®, and N-Gamimune®.
• High-titer antibody solutions to hepatitis B surface antigen can be derived from antibody-carrying donor plasma
• Using human immunoglobulin solutions prevents general or specific infections, known as passive immunization.
• These intravenous and/or intramuscular injections can cause anaphylactic shock.
• Animal immunoglobulins: Anti-thymocyte equine immunoglobulin (ATGAM®) manages allograft rejection in renal transplant patients by reducing T-lymphocytes and suppressing cell- and humoral-mediated immunities; administered via IV infusion with other immunosuppressants.
• Monoclonal antibodies: Mouse monoclonal anti-CD3 antibodies, like OKT3®, are used to remove cytotoxic T cells to prevent kidney transplant rejection.
• Potential Anaphylaxis should be carefully monitored when administering animal immunoglobulins for therapy.

Antibodies as Drug Carriers

• Antibodies, though not cytotoxic, effectively target antigen-bearing cells with high affinity and specificity.
• Antibodies ensure selective delivery of drugs to diseased tissues or cells.
• Bioactive agents with high systemic toxicity or low target tissue absorption benefit from antibody carriers, categorized as:
  • Therapeutic drugs (chemoimmunotherapy)
  • Toxins (immunotoxins)
  • Radionuclides (radioimmunotherapy)

Therapeutic Drugs - Chemoimmunotherapy

• The anti-tumor activity of alkylating agents like chlorambucil may be enhanced if co-administered with an anti-tumor antibody.
• Achieving drug targeting needs covalent linkage of a drug to an antibody molecule. The binding must be stable enough to keep the drug and antibody together before binding with tissues.
• Cancer chemotherapeutic drugs need internalization of surface-bound drug-carrying antibody-antigen complexes via endocytosis to act on intracellular sites like DNA or enzymes.

Toxins - Immunotoxins

• In cancer chemotherapy, cytotoxicity guides drug selection and relies on differentiated toxicity between normal and malignant cells.
• Linking a highly toxic agent to an antitumor antibody selectively delivers it to the tumor, sparing normal tissues and achieving tumor cell killing.
• Non-therapeutic toxic agents are joined with antibodies for treatment.
• Immunotoxins are derived from plant or bacterial protein toxins.
• Used for malignant disease, they are now trialing for autoimmune disease and also graft verses host prevention.

Radionuclides - Radioimmunotherapy

• Antibodies can carry radioactive nuclides for targeted delivery to specific antigen-bearing tissues or cells in cancer treatment.
• Radioimmunotherapy has proven effective for treating liver cancer and lymphomas, and is successful in targeting specific tissues.
• Successful radioimmunotherapy needs a suitable radionuclide, with the ideal half-life.
• Emitted radiation should largely consist of alpha and beta radiations due to their low penetration ability, contrary to radioimmunodection. Gamma rays have high penetration and can damage distant normal tissues.

Antibody Therapeutic Applications: Safety and Efficacy

• Immunoglobulins from human serum should be screened for potential pathogens, like hepatitis B and A, HIV, and lethal viruses.
• Hypersensitivity is a common side effect of antibodies as drugs or drug carriers in patients.

Limitations of Therapeutic Agents

• Impermeability of endothelium: Antibodies are inaccessible to target tissues
• Poor tissue penetration: antibodies are inaccessible to entire tissue
• Antigen heterogeneity/modulation: Antibodies are ineffective to antigen modulated cells
• Lack of antigen on cells: Side effects to normal cells
• No human antibodies: Hypersensitivity towards animal immunoglobulins

Cytokines and Immunotherapy

• Cytokines: Hematopoietic growth factors (HGF) regulate immune system cells.
• Lymphokines: Interleukins (IL-1-14 except 3), interferons (α, β, Υ) regulate lymphocytes.
• IL-2: Stimulates cytotoxic T-lymphocytes (CTLs), natural killer (NK) cells for antitumor activity.

Interferons (INF)

• Interferons are cytokines that induce non-specific resistance to viral infections, named for their ability to interfere with viral replication.
• Interferons come in alpha (α), beta (β), and gamma (Y) forms. IFN α from leukocytes, IFN- β and -Y from fibroblasts and then lymphocytes respectively.
• They exert biological activity by viral inhibitor expression antiviral.
• They exert antitumor activity by cellular activation and also MHC class I antigens.
• Human recombinant IFN- α (rhIFN- α) is a commercial treatment that are linked to viral infections.
• Some viruses include Hepatitis B, Hepatitis C, Human T-lymphotropic virus I, Human T-lymphotropic virus II etc
• Tumors: Hepatocellular Carcinoma, AIDS-relared lymphoma, Nasal pharygneal carcinoma etc
• Interferon-ß’s activity is similar to Interferon-a.
• It treats gliomas, breast cancer, and bladder cancer.
• Interferon -ẞ can downregulate T-cell which is different from a.
• It treats autoimmune disorders such as sclerosis.
• Interferon-v shares functional properties that are similar to INF-a and -ß but different to it’s anti properties,
• Recontaminant interferon treats granulomatous disease that affects the lungs.

Transplantation

• Graft refection confronts all organ transplants. The immune system sees the organs as a foreign antigen.
• The heart, kidney, liver, lung, pancreases retina and bone marrow can be used with transplants.

Transplantation according to source

• Autograft: self tissue is transferred through a body site from an individual.
• Isograft: the tissues from genetically identical individuals have been transferred. Allograft: the tissues that have been transferred can be from genetically different members or the same species
• Xenograft: tissues are transferred from different species from humans for an example an ape.

Immunology of Graft Rejection

• Mediates graft with activation of CD4 or CD8 T cells, with macrophages, nutrophilis, and vascular endothelium

Classification of transplant rejection

• Occurs within minutes or hours of supply.
• Mediated with a preformed antibody. At risk will also be multiparous woman individuals or a former use of xenograft.

Hyperacute Rejection CONT'D

• Associated with complement activation, stimulation of coagulation cascade, thrombosis
• ishemia
• Treatment is graft removal.
• Acute : Week post transplant
• T cells
• Rejection : vascular injury, etc.
• Chronic is months and yours but is delayed sensitivity.
• Graft diseases can lead to diarrhea liver failures with bone morrow.
• 50-70% for marrow and a clinical cell donor. Allogins with erythrodemia with failure.
• To counter the effects of Immunosuppressive agents are selective as a agent.

Types of Immunosuppressive Agents

• Corticosteroids are potent for immunity
• Agents : lymphocyte maturation.
• Molecules bind to cells for usage through induction in the immune response.
• *Classical determine the HLC phenotypes. Also done with antibioses and testing.
• Molecules base HLA use PCR for the genotype for amplification.

Immunological test available in pharmacy stores

• COVID-19 Tests
• Streptococcus
• influenza test
• HIV testing
• Hepatitis C viruses with rapid tests for blood in the stool. allerogen tests for allergy
• Tests check for syphilis and cileac.
• Other ones for HIV, and pregnancy
• STI testers also check H. Pylori antibody test
• Dengue fever and RSV are checked
• Mono and rubella are checked to herpes, Make you do not assume that you know how to diagnose with rapids and read the requirements through the test to find issues with the effects with antigens and anti bodies causing false negative or false positive traits

Explore how antibodies act as therapeutic agents, neutralizing toxins and eliminating target cells. Learn about their use in treating infections, poisoning, and drug toxicity, as well as the potential for hypersensitivity reactions. Discover the applications of antibodies in antiserum form for life-saving treatments.