Information about Monoclonal Antibodies
Monoclonal antibodies are antibodies that have a high degree of specificity (mono-specificity) for an antigen or epitope. Monoclonal antibodies are typically derived from a clonal expansion of antibody producing malignant human plasma cells.
Mechanism of action of Monoclonal Antibodies
The initial monoclonal antibodies were created by fusing spleen cells from an immunized mouse with human or mouse myeloma cells (malignant self-perpetuating antibody producing cells), and selecting out and cloning the hybrid cells (hybridomas) that produced the desired antibody reactivity. These initial monoclonal products were mouse antibodies and were very valuable in laboratory and animal research and diagnostic assays, but were problematic as therapeutic agents because of immune reactions to the foreign mouse protein. Subsequently, production of chimeric mouse-human monoclonal antibodies and means of further “humanizing” them and producing fully human recombinant monoclonal antibodies were developed. The conventions used in nomenclature of monoclonal antibodies indicate whether they are mouse (-omab), chimeric (-ximab), humanized (-zumab) or fully human (-umab).
Clinical use of Monoclonal Antibodies
Monoclonal antibodies have broad clinical and experimental medical uses. Many of the initial monoclonal antibodies used in clinical medicine were immunomodulatory agents with activity against specific immune cells, such as CD4 or CD3 lymphocytes, which are important in the pathogenesis of rejection after solid organ transplantation. Subsequently, monoclonal antibodies were prepared against specific cytokines (anti-cytokines), which were believed to play a role in cell and tissue damage in immunologically mediated diseases such as rheumatoid arthritis, alkylosing spondylitis, inflammatory bowel disease, multiple sclerosis and psoriasis, among others. In addition, therapeutic monoclonal antibodies were developed, aimed at blocking or inhibiting the activity of specific enzymes, cell surface transporters or signaling molecules and have been used in cancer chemotherapy and to treat severe viral infections. Use of monoclonal antibodies is currently broadening to therapy of other severe, nonmalignant conditions including asthma, atopic dermatitis, migraine headaches, hypercholesterolemia, osteoporosis and viral or bacterial infections. Thus, the therapeutic monoclonal antibodies do not fall into a single class and have broad therapeutic uses. As of 2018, more than 60 therapeutic monoclonal antibodies are approved and in use in the United States.
Side effects of Monoclonal Antibodies
Monoclonal antibodies are generally well tolerated. Because they are large proteins (typically 150-200,000 daltons in size) they require parenteral, usually intravenous, administration. Circulating proteins are metabolized by many cells, but particularly by hepatocytes. Proteins undergo hepatic uptake by endocytosis and are either degraded or recycled to the cell surface for secretion. The hepatic metabolism of antibodies often determines their half-life. Proteins are broken down by cellular proteases into small peptides and amino acids that can used to synthesize other proteins. Metabolism of proteins does not generate toxic intermediates and, therefore, monoclonal antibodies are unlikely to induce drug induced liver injury via production of toxic metabolites. On the other hand, the peptides that are generated by the metabolism of the exogenously administered protein may ultimately be presented as foreign epitopes and generate an immune response. In addition, the primary effect of the monoclonal antibody may generate a response, either immune or otherwise, that leads to an immune mediate hepatic injury. Finally, monoclonal antibodies that suppress the immune system may cause reactivation of latent infections, including tuberculosis and hepatitis B.
Among the monoclonal antibodies that have been used in clinical medicine, only a few have been linked to drug induced liver injury and, in many situations, the cause of the hepatic adverse event is often unclear. The monoclonal antibodies most clearly linked to drug-induced liver injury include the antibodies to tumor necrosis factor (anti-TNF such as infliximab, adalimumab, certolizumab and golimumab), to antibodies to check point proteins (anti-CTLA4 such as ipilimumab, anti-PD1 such as nivolumab and pembrolizumab and anti- PD-L1 such as atezolizumab, avelumab and durvalumab) and to antibodies to B cell markers and activation signals (anti-CD20 such as rituximab, ofatumumab and tositumomab). The liver injury caused by these products is usually attributed to induction of autoimmunity or to immune modulation and reactivation of hepatitis B.
Because of their fine specificity, monoclonal antibodies can also be used to direct more conventional therapeutic agents to specific organs, tissues or cells. Several monoclonal antibody conjugates have been developed, largely in the therapy of cancer, the conjugated drug being an antineoplastic or cytotoxic agent. Four such agents are gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine and inotuzumab ozogamicin. These products combine a monoclonal antibody (anti-CD33, anti-CD30, anti-HER2, anti-CD22) to a microtubule inhibitor (ozogamicin, vedotin, emtansine). These agents have been associated with serum enzyme elevations during therapy, and several have been linked to hepatic vascular damage, sinusoidal obstruction syndrome and nodular regenerative hyperplasia. These forms of hepatotoxicity are likely due to the conjugate (the "payload") rather than the monoclonal antibody (the targeting vehicle).