New technique enhances binding avidity of MoAbs

VANCOUVER, British Columbia, Canada—New technology from InNexus Biotechnology, known as Dynamic Cross-Linking (DXL), could be used to improve the target-binding affinity of existing monoclonal antibodies (MoAbs) as well as those in development.

The company recently announced laboratory results of its first product candidate DXL625 (CD20), a humanized anti-CD20 MoAb enhanced with DXL technology, being developed for the treatment of non-Hodgkin's lymphoma.

The DXL technique involves modifying a MoAb by adding a small peptide sequence that becomes self-recognizing when two or more MoAb molecules are in close proximity.

This self-binding property causes the modified antibodies to cluster at the target receptor, resulting in greater molecular mass on the surface of the target cell (see Figure).

Preclinical studies have shown that this higher MoAb concentration at the point of attack provides a potency advantage over conventional MoAbs in inducing cell growth inhibition, apoptosis, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity.

The company believes that by achieving a higher concentration of antibody at the antigen target, dose reduction may be possible.

DXL625 was constructed by chemically attaching (cross linking) the DXL peptide to an anti-CD20 antibody. A fusion protein version of the antibody is also being investigated. Results of in vivo studies of DXL625 were presented at the IBC Life Science Drug Discovery and Development of Innovative Therapeutics Conference in Boston.

The studies showed that DXL625 had a higher binding affinity to the target antigen CD20, compared with the unconjugated parent molecule, and a greater ability to induce apoptosis in cell-based assays. In B cell tumor cells, apoptosis was 50% at day 3 for DXL625 vs 12% for the parent antibody.

In three different cell lines, DXL625 resulted in a "remarkable" increase in complement-dependent cytotoxicity, compared with unconjugated anti-CD20, the researchers said, and in DHL-4 and Raji cell lines, DXL625 exhibited greater inhibition of cell proliferation.

Studies also showed that DXL625 did not have significant immunogenicity or toxicity in mice.

Another DXL antibody targeting HER2/neu showed significantly more potency than the parent antibody in slowing tumor progression in a xenograft disease model, the company said.