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Innovative therapeutic antibodies—synthetic variable regions

Inhibrx: A gBlocks® Gene Fragment story

These researchers use gBlocks® Gene Fragments to synthesize antibody variable regions to create novel heavy/light chain combinations. Learn how they do it.

Founded in the spring of 2010, Inhibrx is a biotherapeutic discovery and develop­ment company. Through use of a variety of antibody generation and optimization technologies developed in-house, the Inhi­brx scientists can generate highly optimized therapeutic molecules/leads that target various steps in specific oncological and inflammatory disease pathways.

We spoke to Brendan Eckelman, founder, and vice president of scientific operations at Inhibrx, about their use of IDT gBlocks Gene Fragments. Inhibrx researchers use gBlocks fragments as a fast, inexpensive alternative to cloning target molecules from cDNA libraries or commercial synthesis. The researchers have assembled up to 4 over­lapping gBlocks Gene Fragments in a single PCR to create 1800 bp gene constructs.

More frequently, though, Inhibrx scientists use gBlocks fragments to make smaller con­structs. For example, they use the synthetic gene fragments to synthesize antibody variable regions. Each variable domain is comprised of about 110 amino acids, and thus encoded by just 330 bp. These regions can be generated by inserting a single gBlocks Gene Fragment into an Inhibrx antibody expression construct. Eckelman noted, “gBlocks Gene Fragments have become particularly useful for Inhibrx in our antibody humanization platform. Our researchers use a structural modeling approach that then requires generation of 10−20 variant heavy and light chain sequences for expression in mammalian systems (Figure 1)."

D3.3-YR-InhibRx Fig1
Figure 1. Structural Model of an Antibody VH VL Complex.

"There are no templates in these cases,", notes Dr  Eckelman, "so use of gBlocks Gene Fragments provides a unique solution that has greatly augmented the efficiency of this project. Overall the gBlocks technology is a very suitable and less expensive alterna­tive to gene synthesis, and often it is more efficient than cloning from cDNA.”

Another application of gBlocks Gene Fragments for Inhibrx scientists is the generation of cognate antigens from various species. Frequently, the antigen of interest is not well represented in cDNA libraries from a particular species or the cDNA is not readily available. The gBlocks technology allows the Inhibrx scientists to just create the sequence they need and rapidly clone it into one of their expression vectors.

Research profile

A founder of Inhibrx, Brendan Eckelman, PhD, is vice president of Scientific Operations. Dr Eckelman has substantial drug development experience with specific expertise in protease biochemistry, cell death signaling pathways, and protein engineering. He pioneered the development of the Inhibrx VAST-mAb™ platform and numerous other antibody development, engineering, and optimization technologies. His research interests surround creating novel methods for immune recruitment and activation for cancer therapy. In addition, he has established a unique bifunctional biologics platform aimed at inflam­matory disease treatment.

Prior to founding Inhibrx, Dr Eckleman was a research investigator in the biotherapeutics group at the Genomics Institute of the Novartis Research Foundation (GNF). Dr Eckleman re­ceived his PhD in molecular pathology from the University of California, San Diego School of Medicine and conducted his graduate research at the Sanford-Burnham Medical Research Institute.

Published Jul 8, 2013
Revised/updated Jun 19, 2015