Scripps research generates novel humanised mAb with strong affinity and specificity for ROR2

Lab cell culture

Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens that are solely present on cancer cells that can serve as useful targets. One such antigen – receptor tyrosine kinase-like orphan receptor 2 (ROR2) – is normally expressed only during embryogenesis and then is tightly down-regulated, however, it is up-regulated in a diverse set of cancers. This includes solid malignancies such as renal cell adenocarcinoma and subsets of breast cancer, as well as hematologic malignancies, such as multiple myeloma. As such, ROR2 represents a promising candidate antigen for antibody-based cancer therapy.

Previous research by the Scripps Research Institute had identified several potential ROR2 antibody candidates by mining a large library of novel rabbit antibodies (>10 billion) that had been generated through phage display. Now a new paper by the same team, describes the process and results of affinity maturation and humanization of one of these rabbit mAbs. The candidate antibody was selected as it binds both human and mouse ROR2 but not to other human cell-surface antigens including human ROR1 (which has 58% amino acid sequence identity with ROR2).

The affinity matured and humanized mAb maintained strong affinity to ROR2. It was also shown to retain its specificity to ROR2 when screened against 5,500+ plasma membrane and secreted protein targets using the Retrogenix human cell microarray platform. Following conversion to a T-cell engaging bispecific antibody, the ROR2 candidate displayed potent cytotoxicity toward ROR2-expressing cells.

The authors anticipate that this humanized affinity matured mAb will find application for antibody-based therapy of ROR2-expressing cancers. The paper, co-authored by Scripps researchers and scientists from Retrogenix, has been published in the Journal of Biological Chemistry. Please click here for the abstract and full text options.

To find out more about the previous Scripps project on the generation of novel rabbit mAbs, please see here

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