Proteins therapeutics are well established as a clinically and commercially important class of new medicines. Our deep experience in protein engineering has provided a better understanding of their strengths and limitations, leading to new technologies to improve and develop better protein drugs. Protelica is developing the next generation of protein therapeutics called Pronectins™ which is a new format of engineered protein scaffolds. The development of Pronectins™ will take advantage of the enhanced antibodies, such as optimized Fc fusion proteins, bispecific and antibody drug conjugates in early clinical development. Pronectins™ will feature many advantages over antibodies with enhancements related to more efficacy, greater safety, no immunogenicity or improved delivery. Pronectin™ therapeutic products offer the following features:
High affinity, specific binding to a therapeutic target with only a single Pronectin™ domain
Enhanced efficacy with greater potential to specifically modulate multiple therapeutic targets for multiple therapeutic effects in a single drug molecule
No immunogenicity potential: the Pronectin™ backbone is designed from a naturally occurring human fibronectin protein that has evolved to be tolerated by the human immune system
Broad therapeutic applications by creating Pronectins™ to many target types, including targets that are hard to drug by antibodies or small molecules.
Protelica has developed a number of patented DNA mutagenesis technologies for protein affinity maturation: Walk-Through Mutagenesis™ (WTM), Look-Through Mutagenesis™ (LTM) and Combinatorial Beneficial Mutation™ (CBM). The processes use a rational, chemistry-based approach (amino acid side chains) to build “intelligent” libraries and develop protein analogs with improved affinities. Traditional DNA mutagenesis approaches involve techniques such as random mutagenesis, saturation mutagenesis, error prone PCR, and gene shuffling. These strategies are inherently stochastic and often require the construction of exceedingly large libraries to comprehensively explore sufficient sequence diversity. Creating these exceedingly large synthetic libraries, however, often results in a high percentage of unproductive variants, leading to candidate screens that are inefficient in both cost and time.
In contrast, our mutagenesis technologies (WTM, LTM, and CBM) are based on a defined DNA synthesis methodology that builds structured, motif-oriented, “intelligent” libraries. The oligonucleotides are designed to precisely execute codon-by-codon modifications and to introduce selected target amino acids systematically and comprehensively into selected positions of the protein. This approach creates protein libraries that comprehensively cover meaningful protein space in a compact design. Our libraries are smaller, very focused, and highly efficient. Moreover, our technology is the only one capable of exploring large protein sequences and producing sequence-function information. We believe that Protelica’s patented mutagenesis technologies produce the highest quality “universal” protein libraries that, in turn, allow for rapid selection of binders to potential targets. Protelica’s Intelligent Mutagenesis is covered by numerous patents and patent applications worldwide.
Pronectins™ are an emerging, proprietary, protein therapeutic class that can be developed to address a broad range of diseases, including cancer, inflammatory and degenerative diseases. Pronectins™ are based on the fourteenth fibronectin type-III scaffold of Human Fibronectin (14Fn3). The well-characterized fibronectin protein is prevalent throughout the human body. Human fibronectin, an extracellular protein, is naturally abundant in human serum. Intelligent loop-diversity has been designed to closely mimic the natural human repertoire and avoid sequence immunogenicity. The intrinsic properties of a Pronectins™ align with the pharmacological properties needed to make it a successful drug, including high potency, specificity, stability, favorable small size, and high-yield production in E.coli and yeast.
Pronectins™ are designed using Protelica’s patented protein design and optimization engine, to achieve high potency and specificity for a therapeutic target while simultaneously selecting for ideal pharmaceutical product characteristics. Protelica is able to screen billions of unique Pronectin™ loop sequences for each drug discovery program and redirect a laboratory designed human fibronectin analog to act as a protein proprietary ligand against a specific therapeutic target. The power of our Pronectin™ platform is distinguished by the synergistic benefit of our universal fibronection type III library design, derived from a bioinformatics analysis of more than 3000 FN3 loop sequences, combined with our patented mutagenesis technologies to create meaningful loop diversity and expand the human repertoire from few thousand to 25 billion new sequences.
Loop diversity is solely generated by the combinatorial effect of a set of naturally/ human occurring amino acids. When combined with the use of statistically preferred loop lengths in Nature, this results in a higher percentage of stable, non immunogenic functional variants. With regard to potential immunogenicity of artificially created loop sequences, we believe our approach has the least risk. Protelica “evolutionary” approach maximizes the use of amino acids selected by nature over the course of millions of years. In addition, since we isolate families of high affinity binders with similar sequences from our library, we can further screen these ligands for lack of potential immunogenicity using in silico, in vitro, and in vivo methods.
Protelica is the exclusive owner of the intellectual property covering the Pronectin™ protein as a novel protein class, the universal library of Pronectin™ and the process to produce its libraries. As Protelica conducts drug discovery, individual therapeutic Pronectin™ programs will give rise to more specific composition of matter product and use protection, providing another layer of protection and an extended period of exclusivity.
In addition, Protelica’s technology and drug discovery platform covers intellectual property related to its DNA Mutagenesis, including Walk-Through and Look-Through Mutagenesis; immunoglobulin protein engineering; and enzyme engineering. Protelica’s portfolio consists of more than seventy patent and patent applications as of May 2017, including key patents granted in the United States, Europe and Asia.
Issued US Patents include the following: US 9,376,483 Universal fibronectin type III binding domain libraries US 9,012,369 Look-through mutagenesis for developing altered polypeptides with enhanced properties US 8,716,195 Antibody ultrahumanization by predicted mature CDR blasting and cohort library generation and screening US 8,697,608 Universal fibronectin type III binding domain libraries US 8.680,019 Universal fibronectin type III binding domain libraries US 8,470,966 Universal fibronectin type III binding domain libraries US 6,649,340 Walk-through mutagenesis US 6,432,675 Combinatorial polypeptide antigens US 5,830,650 Walk-through mutagenesis US 5,798,208 Walk-through mutagenesis
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