Blocking antibody

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A blocking antibody is an antibody that does not have a reaction when combined with an antigen, but prevents other antibodies from combining with that antigen. [1] This function of blocking antibodies has had a variety of clinical and experimental uses.

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The term can also be used for inhibiting antibody, prozone phenomenon and, agglutination reaction.

Blocking antibodies have been described as a mechanism for HSV-1 to evade the immune system. [2]

Uses

Blocking antibodies can be used in a variety of medical and scientific manners, thus far been to treat cancer, Graves' disease, and prevent the growth of malaria in mosquitoes.

Cancer treatment

Blocking antibodies have been used in clinical trials of cancer treatments. The blocking antibody ipilimumab has been effectively used in the clinical treatment of melanoma, RCC, and NSCLC with some degree of success. [3] This is accomplished through the blocking of the coinhibitory molecule CTLA-4. The blocking antibody does not directly target tumor cells, but rather blocks the regulatory functions of CTLA-4, resulting in enhanced T-cell function. [4]

Some new treatments hypothesize the blocking of PD-1, a programmed cell-death protein, which will result in longer-lived T-cells. The blocking antibody BMS-936559 has been shown to bind to PD-L1 and prevent its binding to PD-1. [4]

These new treatments are not without side-effects and irAEs (immune-related adverse events) have been observed in a variety of patients. The tolerance that immune cells normally have to host tissues can be lost, resulting in permanent damage to host cells. [4]

Graves' disease

Studies have shown that blocking antibodies can bind to and prevent thyrotropin binding, resulting in reduced cAMP levels in human thyroid cells. This interaction has been used primarily as a method of indicating that Graves' disease immunoglobulins are pluritopic, meaning that they have multiple effects, rather than indicating a possible treatment for this disease. [5]

Malaria

Blocking antibodies have a variety of functions on the merozoite form of parasitic malaria. While in the merozoite form, malaria parasites invade erythrocytes and reproduce in them. Some blocking antibodies may inhibit the invasion of erythrocytes, while other blocking antibodies prevent the binding of inhibitory antibodies, allowing merozoite invasion of erythrocytes despite the presence of inhibitory antibodies. The monoclonal antibodies that prevent the invasion of merozoites bind to the parasitic antigen MSP-1 (merozoite surface protein 1). The binding of blocking antibodies to MSP-1 is shown to result in the inhibition of secondary processing, resulting in the inability for merozoites to invade host erythrocytes. [6] Secondary processing involves a single proteolytic cleavage on the merozoite surface of the carboxy-terminal component of MSP-1. [7] The blocking of MSP-1 has been proposed to be a method of creating a vaccine against malaria by preventing its invasion and multiplication.

See also

Related Research Articles

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Immunosuppressive drug

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications are drugs that inhibit or prevent activity of the immune system.

Monoclonal antibody Monospecific antibody that is made by identical immune cells that are all clones of a unique parent cell

A monoclonal antibody is an antibody made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.

<i>Plasmodium falciparum</i> Protozoan species of malaria parasite

Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans. The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases. P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer and is classified as Group 2A carcinogen.

Cancer immunotherapy Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy is the artificial stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspeciality of oncology.

Merozoite surface protein

Merozoitesurface proteins are both integral and peripheral membrane proteins found on the surface of a merozoite, an early life cycle stage of a protozoan. Merozoite surface proteins, or MSPs, are important in understanding malaria, a disease caused by protozoans of the genus Plasmodium. During the asexual blood stage of its life cycle, the malaria parasite enters red blood cells to replicate itself, causing the classic symptoms of malaria. These surface protein complexes are involved in many interactions of the parasite with red blood cells and are therefore an important topic of study for scientists aiming to combat malaria.

CTLA-4

CTLA4 or CTLA-4, also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.

Monoclonal antibody therapy Form of immunotherapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. More recently antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

Ipilimumab Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Tremelimumab

Tremelimumab is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer, it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca. It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.

Malaria vaccine Vaccine that is used to prevent malaria

A malaria vaccine is a vaccine that is used to prevent malaria. The only approved vaccine as of 2021 is RTS,S, known by the brand name Mosquirix. It requires four injections, and has a relatively low efficacy. Due to this low efficacy, the World Health Organization (WHO) does not recommend the routine use of the RTS,S vaccine in babies between 6 and 12 weeks of age.

Medarex was an American biopharmaceutical company based in Princeton, New Jersey, with manufacturing facilities in Bloomsbury and Annandale, New Jersey, and research facilities in Milpitas and Sunnyvale, California. In 2009, Medarex was purchased by Bristol Myers Squibb.

Chemoimmunotherapy is chemotherapy combined with immunotherapy. Chemotherapy uses different drugs to kill or slow the growth of cancer cells; immunotherapy uses treatments to stimulate or restore the ability of the immune system to fight cancer. A common chemoimmunotherapy regimen is CHOP combined with rituximab (CHOP-R) for B-cell non-Hodgkin lymphomas.

A bispecific monoclonal antibody is an artificial protein that can simultaneously bind to two different types of antigen. Naturally occurring antibodies typically only target one antigen. BsMabs can be manufactured in several structural formats, and current applications have been explored for cancer immunotherapy and drug delivery.

Programmed cell death protein 1

Programmed cell death protein 1, also known as PD-1 and CD279, is a protein on the surface of cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most commonly alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.

Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic – tropical and subtropical geographic areas.

An immune checkpoint regulator is a modulator of the immune system, that allows initiation of a productive immune response and prevents the onset of autoimmunity. Examples of such a molecule are cytotoxic T-lymphocyte antigen 4, which is an inhibitory receptor found on immune cells and programmed cell death 1 (CD279), which has an important role in down-regulating the immune system by preventing the activation of T-cells.

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of proteins present on the membrane surface of red blood cells that are infected by the malarial parasite Plasmodium falciparum. PfEMP1 is synthesized during the parasite's blood stage inside the RBC, during which the clinical symptoms of falciparum malaria are manifested. Acting as both an antigen and adhesion protein, it is thought to play a key role in the high level of virulence associated with P. falciparum. It was discovered in 1984 when it was reported that infected RBCs had unusually large-sized cell membrane proteins, and these proteins had antibody-binding (antigenic) properties. An elusive protein, its chemical structure and molecular properties were revealed only after a decade, in 1995. It is now established that there is not one but a large family of PfEMP1 proteins, genetically regulated (encoded) by a group of about 60 genes called var. Each P. falciparum is able to switch on and off specific var genes to produce a functionally different protein, thereby evading the host's immune system. RBCs carrying PfEMP1 on their surface stick to endothelial cells, which facilitates further binding with uninfected RBCs, ultimately helping the parasite to both spread to other RBCs as well as bringing about the fatal symptoms of P. falciparum malaria.

Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.

References

  1. ↑ Blocking+Antibodies at the US National Library of Medicine Medical Subject Headings (MeSH)
  2. ↑ Hook LM, Huang J, Jiang M, Hodinka R, Friedman HM (July 2008). "Blocking antibody access to neutralizing domains on glycoproteins involved in entry as a novel mechanism of immune evasion by herpes simplex virus type 1 glycoproteins C and E". J. Virol. 82 (14): 6935–41. doi:10.1128/JVI.02599-07. PMC   2446985 . PMID   18480440.
  3. ↑ Callahan, Margaret (March 26, 2013). "At the Bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy". Journal of Leukocyte Biology. 94: 41–53. doi:10.1189/jlb.1212631. PMC   4051187 . PMID   23667165.
  4. 1 2 3 Kyi, Chrisann (October 23, 2013). "Checkpoint blocking antibodies in cancer immunotherapy". Federation of European Biochemical Societies Letters.
  5. ↑ Valente, William (July 19, 1982). "Monoclonal antibodies to the thyrotropin receptor: Stimulating and blocking antibodies derived from the lymphocytes of patients with Graves disease". Proceedings of the National Academy of Sciences. 79: 6680–6684. doi:10.1073/pnas.79.21.6680. PMC   347192 . PMID   6292912.
  6. ↑ Uthaipibull, Chairat (April 13, 2001). "Inhibitory and blocking monoclonal antibody epitopes on merozoite surface protein 1 of the malaria parasite Plasmodium falciparum". Journal of Molecular Biology. 307: 1381–1394. doi:10.1006/jmbi.2001.4574.
  7. ↑ Blackman, MJ (July 1996). "Plasmodium knowlesi: secondary processing of the malaria merozoite surface protein-1". Experimental Parasitology. 83: 229–39. doi:10.1006/expr.1996.0069. PMID   8682191.
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