Designed for Inherent Quality Based on Best Clinical Antibodies Highly Developable Antibodies Most Affinities Less Than 10nM Broad Paratopic / Epitopic Diversity In House Proprietary Designs Your Custom Library Designs Unique Donors • Exclusive Diversity
Gen 3 Platform
Specifica's Generation 3 Library Platform has quality built in by design. Developability, extremely high diversity, and the exclusion of sequence liabilities are intrinsic to the five libraries making up the Platform, each of which is based on a therapeutic antibody scaffold chosen for its biophysical properties, lack of liabilities and germline gene variety. Diversity is all derived from natural CDR sequences: HCDR3s are amplified directly from purified B cells, while replicated natural CDRs, derived from Specifica's databases, are used for the rest.
The use of natural CDR sequences alone, rather than combinatorial diversity, ensures correct folding, avoids co-variance violations, and allows the complete elimination of sequence based liabilities for five of the six CDRs. As a result of the high functionality of our Generation 3 Library Platform, you can expect a broad diversity of different antibodies from your selections, most of which will have affinities below 10 nM, combined with developability properties usually at least as good as the clinical candidate antibodies from which they were derived. We construct each Generation 3 library de novo, ensuring your library comprises a unique combination of naturally replicated CDRs, combined with at least one hundred million unique HCDR3s derived from a donor pool used only once, guaranteeing each supplied Generation 3 Library Platform is one of a kind.
The majority of antibodies selected directly from the Generation 3 scFv Library using the combined phage and yeast protocol have affinities below 10nM, with ~20% having affinities in the sub-nanomolar range.
Inherent within the design and construction of the Generation 3 Platform is the ability to select high affinity, drug-like, therapeutic antibodies directly from the naive libraries, without the need for downstream optimization. Confirmation of desired developability characteristics of selected antibodies was assessed by the expression of full length IgGs from selected antibodies and testing for: HEK titer, Tm, salt-gradient affinity capture self-interaction nanoparticle spectroscopy, ELISA on a panel of commonly used targets, cross-interaction chromatography and size-exclusion chromatography within the context of accelerated stability. All full length IgG tested to date behave as well as, or better, than the therapeutic scaffolds from which they are derived.
Antibodies selected from our Generation 3 Library Platform show broad paratopic diversity by next generation sequencing of antibody populations fully positive for targets of interest. We translate the extensive sequence dissimilarity into clontoypes, or clusters, using proprietary machine learning algorithms, within which different variants are found. 500-3,000 different clonotypes are usually identified from a phage + yeast selection in which the five libraries are combined, with Levenshtein distances between different clonotypes illustrated below. Paratopic diversity can be maximized still further if libraries are used separately, rather than combined. This extensive clonotypic diversity provides antibodies against a wide variety of target epitopes important for drug efficacy, as well as variants within the clonotypes that allow exploration of the role of affinity modulation.
Levenshtein distances between different antibody clonotypes selected against a therapeutic target for differing numbers of CDRs, from all six (left) to LCDR3 only (right).
Specifica is using the Generation 3 Platform to generate neutralizing antibodies against SARS-CoV-2 spike protein.