Håkan Mellstedt, M.D., Ph.D. Karolinska University Hospital (Sweden)

NEW ANTIBODIES AND MRD

The tyrosine kinase receptor ROR1 - a potential target for Mab Therapy of CLL

Grant Awarded in 2008

Abstract:

Various acquired functional abnormalities are responsible for the behaviour of malignant cells. Members of the receptor tyrosine kinase (RTK) families contribute to the malignant cell behaviour; these enzymes are important structures to be explored for new therapeutic interventions.

RTK has not been previously described in CLL. However, in a recent report on the gene expression profile of CLL, we noticed that the RTK ROR1 was markedly increased compared to normal B-cells. Based on this preliminary observation, we have initiated a large project to characterize ROR1 in CLL and to develop agents targeting ROR1.

There is not much information on the function of ROR1 and few tools are available for analyses e.g. monoclonal antibodies. An important part of the study is to raise antibodies against ROR1 for analytical purposes.

Expression patterns of ROR1 protein will be measured in CLL as well as other leukemias and in normal cells. Activated forms of ROR1 will also be evaluated in these samples. Modifications of the ROR1 protein that can be seen in similar proteins with abnormal function will also be studied.

ROR1 is present on the surface of CLL cells; monoclonal antibodies will be generated against different parts of the surface ROR1. Preliminary results are promising, and the antibodies will be tested to see if they kill CLL cells. The events which are evoked by these antibodies leading to cell death will be analysed. When a therapeutic candidate has been selected, collaboration with a biotech company will be initiated for the production of a human monoclonal antibody for treatment.

ROR1 is a promising target for specific treatments of CLL, not only antibodies but also later small molecules and vaccines.