Passive immunization in the broadest sense represents the transfer of antibodies to a human recipient who is unable to produce the antibody due to the acuity of an infection, immunodeficiency, or immune tolerance to the target antigen. The use of plasma from patients who have recovered from Ebola or SARS-CoV-2 viruses to treat those acutely ill with these infections is an example of the simplest form of antibody transfer, where neither the antigenic epitope nor the sequence of the antibodies are known, and there is no purification step. Indeed, the pathogen need not be identified; it is only necessary that antibodies can clear the infection. It is critical, however, that the antibodies not paradoxically increase viral infectivity, as thought to occur in dengue infections.

With the use of IVIg (described earlier) to normalize IgG levels in patients with inherited immunodeficiencies (e.g., CVID or X-linked hypogammaglobulinemia) or chronic lymphoproliferative disorders, the goal is to provide a wide range of IgG immunoglobulins specific for antigens encountered by the general population, using a product purified from plasma donated by a large pool of healthy donors. Specialized IVIg products have also been developed that are enriched for antibodies that recognize specific pathogens by prescreening donors. Examples include VariZIG (for varicella), CytoGam (CMV), HBIG (hepatitis B) as well as products for rabies, botulinum toxin, and tetanus.

Immunized animals once served as the major source of therapeutic immunoglobulins; indeed, the modern medical era can be traced to the late 1800s, when serum from horses immunized with diphtheria toxin was first used therapeutically. The antigen used to immunize the animal need not be infectious: antivenom products can be used to treat bites from coral snakes, pit vipers, black widow spiders, and scorpions. Some of these products are treated with proteolytic enzymes to produce Fab fragments, such as for the anti-venom product crotalidae polyvalent immune FAB (CroFab). Digibind is another such Fab product, derived from sheep immunized with digoxin bound to human albumin, and is used to treat digoxin overdoses.

When the intended antigen is of human origin, there is the challenge that human plasma donors are likely to be tolerant to the antigen. A notable exception is the Rh-D antigen, which, being genetically polymorphic, is immunogenic to Rh-negative individuals, and human-derived anti-Rh preparations can be used to prevent sensitization during pregnancy and also as a treatment for immune thrombocytopenic purpura. However, apart from this special case, targeting human antigens traditionally required a sensitized animal, a prominent example being antithymocyte globulin (ATG). Here, purified serum products from animals sensitized with human thymocytes can induce lymphopenia as a treatment for aplastic anemia or as part of an immunosuppressive regimen in organ transplantation.

Polyclonal antibodies can be advantageous in some cases (especially for ATG and antivenin), but the epitopes recognized and the biologic activity may be variable between different lots of the product. In retrospect, then, it is not surprising how Kohler and Milstein ’s technique for the generation of monoclonal antibodies quickly revolutionized medical diagnostics and almost all of biomedical research. Monoclonal antibodies as therapies came more slowly, and there were initial concerns about the generation of “HAMA” (human antimouse antibodies). However, now there are modifications to partially or fully replace mouse sequences with human sequences ( Fig.1A ). Furthermore, fully human antibodies can be generated using mice that are lacking mouse immunoglobulin genes and are transgenic for the human sequences. Using mice with a germline knockout for the gene encoding the antigen of interest can enable the generation of antibodies that have been previously difficult to obtain.  Four fully human monoclonal antibody products (ranibizumab, adalimumab, belimumab, and ramucirumab) now on the market were developed by an alternative method, phage display (see Fig. 1B ). Human antibodies can also be obtained from isolated human B cells that are immortalized by EBV or fusion with an appropriate cell line, and from which immunoglobulin sequences can be obtained by RT-PCR.

Fig1. GENERATION, STRUCTURE, AND MODIFICATION OF MONOCLONAL ANTIBODIES. To generate monoclonal antibodies, based on the technique of Kohler and Milstein, first, a mouse is immunized repeatedly with the antigen, using an adjuvant. After verification of an antibody response, the spleen is removed. Polyethylene glycol is then used to fuse isolated splenic lymphocytes with a mouse nonsecretory myeloma cell line carrying a mutation in the X-linked Hgprt gene, which is essential for the purine salvage pathway. The mutation ensures that the myeloma cell line will not grow in HAT (hypoxanthine, aminopterin, thymidine) media. Normal cells can survive despite the presence of aminopterin, which disrupts the de novo purine syn thesis pathway, because they have an intact purine salvage pathway and can use hypoxanthine. (Because aminopterin interferes with folate metabolism, which also affects pyrimidine synthesis, provision of thymidine is required.) Fusions (hybridomas) between the lymphocytes and the myeloma cell line can grow in HAT only if they have incorporated an X chromosome with the normal Hgprt gene from the mouse lymphocyte, restoring the purine salvage pathway. Unfused lymphocytes, on the other hand, have no stimulus to grow. Hybridomas growing in HAT are then cloned by limiting dilution (e.g., in 96-well plates); some of these hybridomas will have retained the chromosomes containing the rearranged immunoglobulin light and heavy chain of the original lymphocyte. Because these genes are now present in a plasma cell with the cellular apparatus for immunoglobulin secretion, immunoglobulin expressed by the original mouse lymphocyte will now be secreted into the media. The supernatant of each hybridoma clone must be screened for the presence of the desired antibody.

Monoclonal antibodies can affect target cells by activation induced cell death, blockage of ligand-receptor interactions, activation of complement, antibody-dependent cell-mediated cytotoxicity, and uptake of antibody-coated cells in the reticuloendothelial system. To increase cytotoxicity, immunoglobulins can be conjugated to tox ins (e.g., brentuximab vedotin, targeting CD30; trastuzumab emtansine, targeting human epidermal growth factor receptor 2 [HER2]; and gemtuzumab ozogamicin, targeting CD33), belantamab mafodotin, targeting BCMA, and loncastuximab tesirine, targeting CD19), or radionuclides (e.g., ibritumomab tiuxetan or I131-tositumomab). In some of these cases the toxicities are largely the result of the toxin conjugate.

A chimeric molecule consisting of bispecific single chain variable antibody sequences (scFvs) has been developed (blinatumomab), to engage cytotoxic CD3 + T cells with CD19 expressing acute lymphoblastic leukemia (ALL) cells. Similarly, bispecific molecules can approximate two clotting proteins in patients with hemophilia. Faricimab and amivantamab are bispecifics that are designed to inhibit 2 targets simultaneously with one drug. Tebentafusp is a bispecific that engages T cells with uveal melanoma cells, where one moiety is an scFV that binds to CD3, and the other moiety is a fragment of a TCR that recognizes gp100 in the context of HLA A*02:01 on the target cells of individuals who express that HLA allele. A particularly interesting development is the use of single chain antibodies derived from camel “heavy-chain only” immunoglobulin sequences: the smaller molecular size was considered to be advantageous in the development of a drug for TTP targeting a very large molecule, vWF. Obinutuzumab kills CD20-positive cells through a mechanism somewhat different from rituximab due to glycoengi neering such that its Fc moiety has increased affinity for Fc receptors. As for some IVIg preparations, the combination of monoclonal antibodies with hyaluronidase has allowed for subcutaneous injections for increased convenience (e.g., for anti CD20 therapy) and has been accompanied by fewer reactions in the case of anti-CD38 therapy. Antibodies can be engineered for longer half-life as described below in the case of C5 complement inhibition, for increased patient convenience and for more stable pharmacodynamics.

Regarding their antibody-secreting hybridomas, Kohler and Milstein wrote in 1975, “such cultures could be valuable for medical and industrial use,” which is probably one the greatest understatements in the history of medicine. Indeed, there are currently almost 100 FDA approved therapeutic monoclonal antibodies that are based upon their work for which they shared in the 1984 Nobel Prize. About half of these products have been approved in the last 5 years. The 2018 Nobel Prize was awarded to Alison and Honjo for the development of immune checkpoint inhibitors as a treatment for cancer—to date, all of these drugs are monoclonal antibodies. This strategy has opened up new options for patients with Hodgkin disease in addition to solid tumors. mAbs targeting malignant or autoantibody producing blood cells have impacted practically every hematologic, malignant, and autoimmune condition and allogeneic transplantation. In addition to surface molecules, mAbs can target plasma components—in theory, any protein—and this may increase their clearance from the circulation and inhibit protein-protein inter actions or ligand-receptor binding. Antibodies binding to plasma proteins are approved to treat hemophilia, sickle cell disease, TTP, hypereosinophilia, and complement disorders (described below) and to reverse dabigatran anticoagulation. Omalizumab is a special case of a humanized IgG immunoglobulin molecule that targets a whole class of immunoglobulin: IgE.

The side effects of any monoclonal or polyclonal antibody therapy depend on the source of the antibody, the target, and the dose. The administration of human-derived IVIg, which involves a very large dose of immunoglobulin, is typically preceded by acetaminophen and diphenhydramine, and sometimes famotidine, to prevent infusional reactions, as described above. For products derived from animal serum, anaphylactoid reactions are commonly seen, requiring premedication regimens that include high-dose steroids, for example, for equine ATG administration. When the patient later makes an antibody response against horse proteins, this can result in immune complex deposition, leading to serum sickness, characterized by fever, rash, and arthritis. Purified chimeric, humanized, or human monoclonal antibodies will typically not result in these reactions. Rather, side effects are dependent, typically, on “on target” effects. Notable examples of this are the febrile infusion reactions that occur with the initial use of rituximab caused by the lysis of CD20-expressing (malignant and nonmalignant) B cells, the immunosuppressive effects of drugs targeting TNF- α , C5, and integrins, and the bleeding risk associated with targeting von Willebrand factor in TTP. Indeed, one of the worst disasters in the history of drug development was due to the excessive “on target” effect of a monoclonal anti-CD28 antibody. However, a true “off target” side effect could, theoretically, occur if a mAb were to cross-react with unintended epitopes on plasma proteins or extra cellular surface proteins. Monoclonal antibodies can sometimes be detected on an immunofixation, which can confound the analysis of minimal residual disease in multiple myeloma. Because red cells express CD38, administration of daratumumab and isatuximab are detected as panagglutinins which can mask the development of true allo-immunization.

The overall half-life of IgG is approximately 20 days; when targeting an abundant surface protein or rapidly produced plasma protein, the half-life may be shorter. Most monoclonal antibodies are administered less often than weekly; based on their affinity constants, doses required are generally high enough that, with some exceptions (e.g., the antibody-hyaluronidase combinations), they must be given by intravenous rather than subcutaneous injection. The naming of monoclonal antibodies follows a convention such that the first syllable is coined by the company developing the drug, the second syllable indicates the use (e.g., “ci,” for “cardiovascular,” “li” for “immune system,” “tu” or “ta” for “tumor,” and “so” for bone) and the penultimate syllable indicates whether the antibody is derived from mouse sequences (“–omab”), chimeric mouse-human sequences (“ ximab”), more fully humanized molecules (“–zumab”), or fully human sequences (“–umab”). For example, cetuximab is a chimeric antibody used to treat tumors, whereas eculizumab is a humanized antibody that targets the immune system.

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مواضيع ذات صلة

Adverse Events Related to Intravenous Immunoglobulin Infusion

Therapeutic use of Immunoglobulin : Intravenous Immunoglobulin

Immunoglobulins

Complement and Cancer

Complement and T-Cell Immunity

Focusing Antigen on Follicular Dendritic Cells

B-Lymphocyte Coreceptors

The Complement System : Alternative Pathway

The Complement System : Lectin Pathway

The Complement System: Classical Pathway

Secondary Lymphoid Tissue

The Hematopoietic Microenvironment