Nanobodies as novel cancer therapeutics

Rakava obolenja predstavljajo drugi najpogostejši vzrok smrti. V letu 2018 so terjala kar 9,6 milijonov življenj po svetu, od tega 6,4 tisoč v Sloveniji. Bolezen je izjemno kompleksna in zahtevna za zdravljenje, saj se rakave celice z različnimi mehanizmi zaščitijo pred akterji bolnikovega imunskega sistema in učinki terapije. Slednja navadno vključuje obsevanje ali kemoterapijo, v primeru trdnih tumorjev se ti lahko odstranijo tudi kirurško. Težava prvih dveh načinov zdravljenja leži v njuni nespecifičnosti, zaradi katere se poškodujejo tudi zdrave celice, bolnik pa ob tem doživlja neprijetne ali nevarne neželene učinke. Napredek v onkologiji predstavlja odkritje monoklonskih protiteles, ki preko vezave na antigene rakavih celic zagotavljajo usmerjenost zdravljenja. Kljub ciljnemu delovanju se pri njihovi uporabi srečujemo z izzivi, kot so imunogenost, nizka stabilnost in topnost ter neučinkovito in neenakomerno prodiranje v tumorsko maso. Zaradi teh lastnosti je potreba po novih oblikah imunoterapije vedno izrazitejša. Rešitev bi lahko predstavljale variabilne regije kameljih težkoverižnih protiteles oziroma nanoprotitelesa. Slednja kljub odsotnosti variabilne regije težke verige ohranjajo visoko afiniteto vezave. Prav tako je zanje značilna majhna molekulska masa, ki vodi v boljši prehod v tumor, visoka stabilnost v različnih okoljih, visoka topnost in nizka možnost agregacije ter nizka imunogenost. Večina nanoprotiteles za zdravljenje raka je trenutno še na stopnji raziskovanja, nekaj pa jih je že v predkliničnih in kliničnih fazah. Rezultati testiranj so obetavni in navadno boljši od mnogih že odobrenih monoklonskih protiteles. Nanoprotitelesa bi tako v prihodnosti lahko izboljšala zdravilne učinke ali pa celo popolnoma nadomestila klasična monoklonska protitelesa.Cancer is the second most common cause of death globally. In the year 2018 it accounted for 9,6 million deaths worldwide, of which 6,4 thousand occured in Slovenia. The disease is characterized as extremely complex and difficult to treat, as cancer cells use different mechanisms of immune evasion and protection against therapeutics. The leading forms of cancer treatment include chemotherapy and radiation, and surgery in the case of solid tumours. Due to their nonspecific activity, chemo- and radiotherapy damage healthy tissues as well as cancerous ones, which results in the patient suffering from mild to severe side-effects. In this sense, monoclonal antibodies represent a much better treatment option, as their antitumour effects are limited to cancerous cells. While such antibodies offer many advantages, they nonetheless have their limitations, which include relatively high immunogenicity, low stability and solubility, poor tumour penetration and heterogeneous distribution. These properties further highlight the need for new and more optimal immunotherapeutics. Variable regions of camelid heavy- chain antibodies, also known as nanobodies, seem to meet the criteria with their lower molecular mass, which leads to better intratumoural diffusion, high stability and solubility, low tendency to aggregate and low immunogenicity. Furthermore, the lack of the variable region of the heavy chain does not lower their antigen binding affinity. Currently most nanobodies meant for cancer treatment are still in the research phase, but those that passed the first clinical trials seem promising. Due to their superior biological and chemical properties, nanobodies could improve currently available forms of immunotherapy or even replace them completely