CD300f As A Novel Therapeutic Antibody Target For Acute Myeloid Leukaemia

Current outcomes for patient with acute myeloid leukaemia (AML) are unsatisfactory, particularly for older patients where the median overall survival is less than six months. Monoclonal antibodies (mAb) have been used with great success in a range of malignancies and the promising results seen with gemtuzumab ozogamicin suggest they may improve outcomes in AML. CD300f is an immunoregulatory leucocyte cell surface molecule with myeloid restricted expression, which we have investigated as a potential antibody target in AML. We found that CD300f is expressed on blasts and leukaemic stem cells (LSC) from the majority of AML patients and that AML cells express multiple isoforms of CD300f. We showed that there is a range CD300f epitopes expressed on healthy and malignant cells, and developed a novel CD300f mAb, DCR2, which has in vitro and in vivo activity against AML. However we showed that CD300f, like CD33, is expressed on haematopoietic stem cells suggesting that targeting this antigen is likely to result in myelosuppression. We also investigated the expression and regulation of other CD300 family members on myeloid cells, with the results suggesting that this family of molecules has the potential to regulate dendritic cell responses. We identified CD302 as another novel target for AML antibodies, again showing its expression on the majority of AML blasts and LSC. Finally, using the HLDA10 panel of mAbs, we investigated the expression of novel and more established AML targets on both healthy and malignant cells. We showed that all of the tested targets are expressed on both healthy and malignant cells. A key issue for products based on these murine mAbs will be establishing the therapeutic window where there is efficacy against AML without excessive toxicity. The binding patterns of DCR2, and the other mAbs investigated in this thesis, will help to drive the preclinical and clinical testing required to achieve this. Keywords: Therapeutic antibody, AML, CD300