Therapeutic antibodies

By Dillon Lim - Medicine Student @ Brasenose College, Oxford

 

Antibodies are proteins produced by B cells that mediate several important functions: the neutralisation of pathogens or toxins, opsonisation (encouraging engulfment of pathogens etc. by phagocytes) and acting as a focus to trigger other immune responses. For decades now, we have been able to produce monoclonal antibodies (mAbs) by fusing a clonally selected B cell (one that has been exposed to an antigen and is now producing specific antibodies against it) with a tumour cell. The resultant hybridoma retains both the antibody specificity of the B cell as well as the near-immortality of the tumour cell, which gives it the ability to churn out large quantities of antibodies for the body to use.


Antibodies in research and diagnostics

Antibodies are used in research all the time, and their use in diagnostics is exemplified in pregnancy tests and, of topical relevance, the lateral flow devices we use to test for the presence of SARS-CoV-2. Since 1986, mAbs have also been used clinically, such as in biologic therapies, which are providing exciting new opportunities for the treatment of a range of conditions.


Attacking cancers

Cancer cells often express two proteins – CTLA4 and PD-L1, which help to inactivate immune cells. Ipilimumab/nivolumab is an anti-cancer combination therapy in which the antibodies act as receptor antagonists. Ipilimumab binds and prevents signalling through CTLA4 on the cancer cell and nivolumab prevents signalling through PD-1 (the immune protein that interacts with PD-L1). The theory is that these antibodies can potentiate immune attacks of tumours. Radioactive payloads conjugated onto the ends of antibodies can also be used for radiotherapy. CD20 is a protein expressed on B cells and can therefore be targeted in B cell lymphomas. As well as rituximab, a standard mAb specific for CD20, we also have ibritumomab tiuxetan, which has the same target but is bound to 90Y on its tail-end. The radioisotope releases β radiation to kill the cancer cells.


Immune suppression

There also exists antibody therapies that are designed to dampen immune responses. This is particularly relevant in autoimmune conditions (where the immune system attacks the body’s own cells). Adalimumab and infliximab are mAbs against TNFα, a cytokine that promotes inflammation. Both of these have been approved for the treatment of a rare condition called ankylosing spondylitis – inflammation of joints of the spine. Eculizumab, a mAb for the C5 protein, which also has inflammatory functions, is used to treat paroxysmal nocturnal haemoglobinuria, a condition where C5 (and some other related proteins) destroy red blood cells. Recently, tocilizumab, another antibody stopping inflammatory signalling, was shown to improve survival in COVID-19 patients, by reducing the effects of the so-called cytokine storm.


Future directions

The nature of monoclonal therapy means that there is a huge range of potential targets yet to be explored. The development of antibodies against pathogens has been slow but deserves more attention; particularly given the increasing levels of resistance in pathogens to conventional drugs. A few examples do exist – palivizumab used against the respiratory syncytial virus, raxibacumab against B. anthracis, and bezlotoxumab against C. difficile.


Finally, it’s worth noting that monoclonal therapies are also being used in combination with traditional drugs. Most of the work in this field has again been in cancer: ipilimumab and conventional radiotherapy together have shown to be more effective than either treatment on its own, as have rituximab and chemotherapy in B cell lymphoma.


Further reading

1. Antibodies.

https://ib.bioninja.com.au/higher-level/topic-11-animal-physiology/111-antibody-production-and/antibodies.html

2. Monoclonal Antibodies.

https://ib.bioninja.com.au/higher-level/topic-11-animal-physiology/111-antibody-production-and/monoclonal-antibodies.html

3. Monoclonal Antibodies (MABs).

https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/targeted-cancer-drugs/types/monoclonal-antibodies

4. Monoclonal Antibodies and Their Side Effects. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/monoclonal-antibodies.html

5. Future Perspectives of therapeutic monoclonal antibodies. https://www.futuremedicine.com/doi/full/10.2217/imt-2018-0130 (advanced)

6. Tocilizumab in COVID-19: some clarity amid controversy. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00712-1/fulltext (advanced)