Team:SDU-Denmark/Tour72
Medical aspects
For peptide aptamers to be implementable in diagnostics and therapy, some challenges have to be accomodated. Antibodies comprise a dangerous threat for microorganisms displaying pathogen-associated molecular patterns (PAMPs). PAMPs are recognized by the antibodies FabFabfragment, antigen-binding-region and induces an immune response through the FcFcfragment, crystallizable-region, that binds effector cells of the immune system. The effector mechanisms include: OpsonisationOpsonisationOpson originates from Grece, where it referrers to a delicious side-dish. In this context it means that antibodies mark pathogens, making them more appetizing for phagocytes (i.e. neutrophils and macrophages), agglutinationAgglutinationAgglutinare is Latin and means "to glue". In the immune response it means that the antibodies bind multiple antigens, creating a cluster which is easier for the phagocytes to process in one portion instead of one by one. and complement activationComplement SystemWhen the system is activated, several proteases begin to cleave proteins that release certain cytokines, toxic to the pathogen. By a cascade of cleavage reactions the result is the production of a so called cell killing membrane attack complex that will destroy the given microbe. among other reactions.
One example of an effector mechanism could be to attach small gold nanoparticles (sAuNPs). sAuNPs have recently shown to be excellent tools for cancer therapy, especially because of their high biocompatibily, large surface-to-volume ratio and strong diffusivity, which ensure that they remain intact while moving through organisms e.g.
Reference:
Kim CS, et al. Cellular imaging of endosome entrapped small gold nanoparticles, 2015 Jun 10;2:306-15. doi: 10.1016/j.mex.2015.06.001. [PubMed]
By attaching sAuNPs to the peptide aptamer it would be possible to detect and attack pathogenic organisms more precisely, such as cancer cells, instead of using the current method of targeted radioactive therapy where adjacent normal tissue can be seriously damaged too.
Reference:
Thorek DL et al. Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models. Int J Radiat Oncol Biol Phys. 2015 Jun 9. pii: S0360-3016(15)00612-4.
doi:10.1016/j.ijrobp.2015.06.001 [PubMed]
Chan MD. Recent Technical Advances and Indications for Radiation Therapy in Low-Grade Glioma. Semin Radiat Oncol. 2015 Jul;25(3):189-96.
doi: 10.1016/j.semradonc.2015.02.001
[PubMed]
If peptide aptamers were to be used as tools in cancer therapy it would require them to be tolerated by the immune system and that they are showing high level of specificity.
One chance of being tolerated by the immune system is by adjusting the size of the protein. The bigger molecule the larger risk of immunogenicityImmunogenicityIf a organism or substance i immunogenic it means that it is able to provoke an response from the human immune system.. If the immune system develops immunization against the peptide aptamer it will not have any function at all. Today, most often mammalian cells are used for production of mAbs, primarily because of their ability to perform post-translational modifications (PTM). Especially N-glycosylation is an important step, resulting in avoidance of the human immune system, i.e. minimizing the risk of immunogenicity. E. coli does not have these specifications yet back in 2002 researches found an N-linked glycosylation system in the bacterium Campylobacter jejuni and demonstrated that a functional N-linked glycosylation pathway could be transferred into E. coli too. Reference: Wacker M et al. N-linked glycosylation in Campylobacter jejuni and its functional transfer into E. coli. Science. 2002 Nov 29;298(5599):1790-3. [PubMed]
Another important fact is the half-life. The half-life ought to be adjustable, if the peptide aptamers should function as treatment for chronic diseases in particular, such as .
Specificity and quality control are some of the most controversial topics regarding the use of antibodies. How can one demonstrate that a given antibody have specificity for a antigen and not anything ells. That would require the researcher to out think any possible substance that the antibody hypothetically could bind and test it - i.e. it is not possible.
| Monoclonal antibodies | Small molecules (e.g. peptide aptamers) | |
| Target specificity | High | Low |
| Size | High molecular weight (~150kD) | Low molecular weigth |
| Targets | Extracellular | Intracellular/extracellular |
| Crosses Blood-Brain Barrier | No | Possibly |