Antibody Research

Immunization of transgenic animals producing human antibodies is by far the most successful approach to obtaining “fully human” therapeutic antibodies. They allow for the rapid generation of candidate antibodies and the ability to transition lead candidates to clinical development without undergoing time consuming steps such as humanization or affinity maturation of antibodies from structural display libraries. In collaboration with Harbour Biomed and utilizing transgenic Harbour H2L2TM mice, Antibody Solutions has generated therapeutic human monoclonal antibody candidates against an immune checkpoint membrane protein target, designated “HBM-1”.

Antibody Solutions performed its first program in OmniAbTM animals in September of 2012. In our 6.5 year history with OminAb animals we have worked with >1000 animals for 27 clients. The purpose of this poster is to update Antibody Solutions history of work with OmniAb animals with an emphasis on work performed in

Immunization of transgenic animals producing human antibodies has been the most successful approach to obtaining fully human therapeutic antibodies. They allow for the rapid generation of candidate antibodies to multiple targets of interest and the ability to transition lead candidates to clinical development without undergoing time consuming and costly steps such as humanization or affinity maturation of antibodies from structural display libraries.

The most robust strategy for therapeutic antibody discovery continues to be through the use of immunized animals and the ability to isolate, interrogate, and/or immortalize immune B-cells. However, capturing the full repertoire of an immunized animal is a challenge that has come to the forefront, particularly as more difficult therapeutic targets have become the industry focus. Various technologies exist for immortalizing and interrogating immune B-cells, though each strategy presents distinct advantages and disadvantages. To this end, Antibody Solutions and Single Cell Technology (SCT) have launched a partnership to integrate SCT’s pioneering single B-cell analysis technology with Antibody Solutions’ comprehensive antibody discovery platform. 

Human antibody-producing transgenic H2L2TM mice have been used to generate monoclonal antibodies to therapeutic targets. Transgenic animals producing human antibodies are by far the most successful approach to obtaining “fully human” therapeutic antibodies. This is largely due to the ability to move transgenic animalderived human antibodies from lead selection directly to clinical development without undergoing lead optimization steps common with humanization of murine Abs or affinity maturation of Abs from phage or other synthetic libraries.

Cystine knot peptides, also know as knottins, are an emerging class of biotherapeutic molecules that can be engineered to bind to a diverse range of targets. Much like therapeutic antibodies, there is a need to develop critical reagents for pharmacokinetic (PK) and immunogenicity assays to support preclinical development, though this new class of molecules can present different challenges and considerations for reagent discovery. To this end, monoclonal and polyclonal reagent antibodies against a cystine-knot fusion protein (CKFP) were generated and used for PK and ADA assay development.

Multi-pass trans-membrane and multimeric membrane proteins are targets for the development of therapeutic monoclonal antibodies. However, they present challenges for expression, antibody generation and screening. Success requires a multi-faceted approach with the following key elements:

• A system for stable expression of the membrane target protein, at high levels, in a variety of cell lines.
• The ability to generate immunogens that present a native, bio-active state with appropriate quaternary structure. Potential immunogens include peptides, soluble protein domains, nanodiscs, proteoliposomes, intact cells, and DNA vectors.
• Effective immunization protocols tailored to the immunogens.
• A robust platform for capturing the antibody response.
• A high-throughput screening platform for detecting antibodies on target protein-expressing cells

Stereochemistry is a fundamental property of proteins that defines their shape and biologic function. Proteins made of L-amino acids have inherent limitations as drugs since they are degraded by proteases which reduce their halflife and are often neutralized by an immune reaction to the protein. Therapeutic proteins made of D-amino acids overcome these limitations since they are inherently resistant to degradation by proteases and have dramatically reduced immunogenicity. Results for VEGF-A and additional therapeutic target proteins are presented

Preclinical and clinical pharmacokinetic (PK) studies require highly specific and high affinity immunoassays to evaluate the safety and efficacy of therapeutic monoclonal antibodies (MAbs). In addition to the requirement that immunoassays specifically detect therapeutic MAbs without interference from host serum proteins, it is increasingly critical to develop reagents that allow differentiation between Free (Unbound) and Total (Bound + Unbound) drug. These reagents help to more fully characterize in vivo drug:target interaction and illustrate the full pharmacologic effect of therapeutic MAbs.

Multi-pass transmembrane and multi-meric membrane proteins are targets for the development of therapeutic monoclonal antibodies, but are often challenging or impossible to express in a native, bio-active state with appropriate quaternary structure. Immunization with surrogate forms of the target including peptides, soluble protein domains, proteo-liposomes, or intact cells are not always successful in producing antibodies that are capable of binding to native state proteins.