Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies (same as immunoglobin) to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).
History
Passive antibody therapy was first propounded by Emil von Behring and Shibasaburo Kitasato in 1890 to treat diphtheria after the observation of immunization in rabbits after injecting serum from tetanus-immunized rabbits. Later in 1891, Paul Ehrlich joined Behring's and Kitasato's research to ameliorate immunizability from lethal toxins. This established the basis of antibody immunotherapy. With the ideology of using antibody serum to treat infectious diseases, the three scientists standardized serum production in dairy cows and merchandised serum vaccines for tetanus and diphtheria. The prevalence of serum therapy surged in the early 19th century. When the H1N1 influenza pandemic (Spanish flu) struck the US and Europe, serum containing antibodies from recovered patients are prevalently injected into patients. With proven therapeutic effects, the applications expanded to other viral and bacterial infections, such as pneumococcus, meningococcus, and rabies, despite an unknown underlying mechanism. Yet, severe anaphylactic reactions and hypersensitivity were common, ergo, serum therapy was pulled out from the market in the 1940s. The resurrection of antibody immunotherapy contributed to Cesar Milstein and Georges J. F. Kohler, who manifested the mass production of pure monoclonal antibodies with limited adverse effects in 1975. Since then, passive antibody therapy has become prevailed as cancer therapeutics and viral treatments.
Classification of passive immunity therapy
Monoclonal antibodies (mAb)
Monoclonal antibodies are manufactured ex vivo from a single B lymphocyte. Serum from immunized animals or humans is first extracted and purified to collect B lymphocytes from the spleen, which are then fused with plasma cell myeloma. After culturing the fused myeloma cell lines, the colonies are selected with the antigens: positive colonies with suitable antibodies can bind to the epitope of the antigen and kill pathogens, whereas colonies without targeted antibodies are eliminated. Upon injection, these homogenous antibodies produced from a single B cell can target a specific epitope on the antigen. The major advantage of using monoclonal antibodies is their specific action towards the target since it only contains one antibody binding site per se, it minimizes cross-reactivity (the activity that antibodies unintentionally bind to non-targeted antigens). However, monoclonal antibodies also mean that overall affinity is lower owing to the limited ability to recognize different epitopes on the antigens, which may lead to incomplete elimination of pathogens and tumor cells. The production time and cost is high as well, limiting its generalizability and prevalence of usage.
Polyclonal antibodies (pAb) The process of manufacturing polyclonal antibodies is similar to that of monoclonal antibodies, which begins with inoculation of antigen conjugate into suitable animals, except multiple B lymphocytes are collected and cultured instead of a single B lymphocyte. Production of polyclonal antibodies circumvents the procedure of ex vivo fabrication of hybridoma cell line and requires minimal purification. The manufacturing cost and time are wherefore reduced. Due to a heterogeneous origin, the antibodies express various subtypes of immunoglobulin against the antigen which has an overall higher affinity and can better detect low-quantity antigens by targeting different epitopes on the antigen. However, it also provokes an increased chance of non-specific reactivity because the antibodies might bind to non-diseases causing substances. In addition, as serum batch may contain various antibodies at different concentrations, it is laborious to corroborate the constituents of every batch.
Mechanism of Action Since some patients fail to produce antibodies effectively and hence have poorer immune responses, passive antibody therapy can reinforce their immune system through the introduction of antibodies from donors. Antibodies are glycoproteins that are naturally produced by the immune system. Each antibody contains four polypeptides of Y shapes and has unique recognition sites of the targets, such as cell surface antigen, and transmembrane proteins on cancer cells and infectious organisms (viruses and bacteria). Upon binding to the antigen, antibodies trigger different cascades to neutralize toxins and kill the cells. There are three ways of action: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).
Antagonistic reaction (Neutralization) and Agonistic reaction Antagonism by antibodies eliminates antigens by binding to the relevant Fc receptors or pathogens for disrupting the toxins from binding to the receptors. In cancers, tumor cells escape immune vigilance by binding to checkpoint proteins on immune cells for inhibiting immune signaling and downregulating the expression of major histocompatibility class I (MHC I). Antagonistic antibodies, also called immune checkpoints inhibitors, obstruct the binding between cancer cells and immune checkpoints to antagonize cancer cells' action and restore immune surveillance. Therefore, immune cells can recognize the surface antigens on the tumor cells to elicit immune responses. Examples of drugs that exploit such a mechanism include pembrolizumab and telimomab.
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