Receptor upregulation enhances cell surface receptor targeted therapies

Abstract

A number of new therapeutic agents for hematologic malignancies have been approved in the last 5 years that target cell surface receptors on the malignant cell. These include a mouse–human chimeric monoclonal antibody to CD20 (rituximab), a 90Y-labeled mouse monoclonal antibody to CD20 (ibritumomab tiuxetan), a humanized antibody to CD52 (alemtuzumab), an immunoconjugate consisting of a humanized antibody to CD33 coupled to calicheamicin (gemtuzumab ozogamicin), and a diphtheria fusion protein (denileukin diftitox) directed at the high affinity interleukin-2 receptor (IL2R) complex [1–5]. In addition, there are a number of targeted protein molecules in various stages of clinical development reactive with various hematopoietic cell surface receptors including CD20, CD22, CD33, HLA-DR, the granulocyte–macrophage colonystimulating factor receptor, among others (see Table 1). Many of these biologics show impressive clinical activity, but most treated patients relapse. To improve the remission rate and duration, one approach has been to combine the biologic compound with cytotoxic drugs [6]. This has yielded outstanding results with rituximab. Another approach is to selectively enhance the potency of the biologic on the target malignant stem cell. Based on both preclinical and clinical data, tumor cell kill with toxin immunoconjugates is proportional to receptor density [7,8]. Foss and coworkers have studied methods to increase the expression of high affinity IL2R on malignant hematopoietic cells to enhance killing by denileukin diftitox [9–11]. In this issue, her group documents that arginine butyrate increases the expression of the subunit of the IL2R on leukemia cells and that this leads to increased sensitivity to denileukin diftitox [12]. Upregulation of receptors on malignant cells is an attractive strategy. This may involve enhanced gene transcription, improved protein stability, or increased protein trafficking to the cell surface. Compounds have been found which modify each of these pathways for a number of receptors (see Table 2). The molecular mechanisms for receptor upregulation by most of these compounds are poorly characterized.