Third Generation pre|CISION^® Peptide Drug Conjugate

Our third class of product candidates consists of pre|CISION^® biologic conjugates. These candidates include those based on coupling of pre|CISION^® warheads to Affimer^® molecules as a means of targeting tumor-specific delivery; and those in which the biologic is intended to further extend plasma half-life. We believe that an Affimer^® that directly targets tumor-associated antigens can lead to further increases in half-life by sequestration of drug molecules prior to activation by FAP. Furthermore, an Affimer^® can be engineered to block signaling within the tumor, such as preventing PD-1/PD-L1 signaling, which we believe may lead to an increase antitumor activity. The attachment of pre|CISION^® cytotoxins to the fragment crystallizable, or Fc, domain of an antibody is expected to increase plasma half-life. The Fc domain has been shown to increase the half-life of molecules in circulation through its interaction with the neonatal Fc receptor, or FcRn. Attachment of an Fc domain to a drug molecule is a modification used to extend the half-life of a number of approved drugs such as Enbrel^®, Eylea^® and Ultomiris^®.^{[1] [2]}

Our Affimer^® drug conjugates

Our Affimer^® molecules are small proteins that can be engineered to bind to a target molecule of interest, in the same way that an antibody does, but with a number of competitive advantages over antibodies. Affimer^® molecules are based on a naturally occurring human protein called stefin A which is engineered to display two loops that create an antigen binding surface. Affimer® molecules are considerably smaller and simpler than naturally occurring antibodies and offer a number of advantages in comparison.

Advantages of Affimer^® molecules compared to antibodies:

• Desired specificity and affinity can be generated more rapidly. Antibodies are often generated by immunization of animals, a process which can take many months. Both the specificity and the affinity of antibodies identified by this method are limited by the immunological response in the particular animals used. By contrast, Affimer molecules are generated by screening a pre-existing library of approximately ten billion candidates, a process which takes weeks.
• Potential to address a broader spectrum of targets. Antibodies that are generated by immunization have some fundamental limitations. These antibodies cannot be generated if they are toxic to the host animal in which they are created. In order to elicit an immune response and to avoid immunogenicity or attack on the animal’s healthy tissues, antibodies must address targets that are sufficiently different than targets endogenous to the animal. These limitations do not apply to Affimer because the screening of potential candidates is done in the laboratory in a process called in vitro phage display that does not use animals.
• Smaller size and simpler manufacturing. Antibodies are typically produced by mammalian cell culture, a time consuming and expensive process. By contrast, as Affimer molecules have no post-translational modifications, thus these molecules can be generated in bacterial cell culture. Along with having a smaller size, they are stable to extremes of pH and temperature, properties that are favorable both for purification and for chemical modification with drug payloads.
• Potential for increased tissue penetration. One of the disadvantages of biologics, such as antibodies, is that their size limits their ability to penetrate poorly vascularized tissues such as tumors.^[3] Affimer monomer molecules are ten times smaller than antibodies, a size advantage that may allow them to penetrate target tissues more readily.
• Engineered for precision modification. Affimer molecules are engineered with specific sites that allow chemical modifications (cysteines), such as attachment of drugs, at specific sites. By contrast, antibodies are naturally occurring molecules that are not optimized for specific chemical modification. This property simplifies the ability to create product candidates that include both Affimer and pre|CISION technologies.

[1] https://link.springer.com/article/10.1007/s40259-015-0133-6/tables/5 
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894971/ 
[3] https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01287/full