CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults

Abstract

CD22 is a surface molecule expressed early during the ontogeny of B cells in the bone marrow and spleen, and can be found on B cells isolated from the different lymphoid compartments in humans. CD22 is expressed by most blasts from the majority (60-90%) of B-cell acute lymphoblastic leukemia (B-ALL). Current therapies in adults with newly diagnosed B-ALL are associated with complete remission (CR) rates of 50-90%. However, 30-60% of these patients relapse, and only 25-40% achieve disease-free survival of three years or more. Chemotherapy regimens for patients with refractory/relapsed B-ALL are associated with CR rates ranging from 31% to 44%. Novel immune-targeted therapies, such as blinatumomab and inotuzumab (a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin), provide potential means of circumventing chemo-refractory B-ALL cells through novel mechanisms of action. Eighty percent of inotuzumab-treated B-ALL patients may achieve a CR state. This review is focused on the biological and clinical activities of CD22 antibodies in B-ALL, and provides evidence about the potential role played by qualitative and quantitative analysis of the CD22 molecule on individual B-ALL blasts in predicting the depletion of leukemic cells, and, ultimately, leading to better clinical response rates.

Keywords: B-ALL; CD22; antigen modulation; inotuzumab.

Figure 1

Genetic landscape of adult B-cell acute lymphoblastic leukemia.

Figure 2

Overview of adult B-cell acute lymphoblastic leukemia treatments.

Figure 3

Structure, interactions, and biological activities of human CD22. The structure of the molecule includes an extracellular domain (six C-type and one V-type immunoglobulin domain). The intracellular domain encompasses immunoreceptor tyrosine-based inhibitory motifs (ITIMs). When sialic acids expressed by antigen presenting cells (APC) bind to CD22, the tyrosine residues of the ITIMs are phosphorylated. Ligation of the phosphorylated ITIMs to Src homology region 2 domain-containing phosphatase-1 and -2 (SHP-1 and SHP-2) and to Src homology region 2 domain-containing inositol phosphatase-1 (SHIP-1) induces a down-regulation of BCR-mediated signaling.

Figure 4

Hypothetical view of the effects induced by the interaction of CD22 with specific antibodies. CD22 can be bound by soluble antibodies as well as by FcR-insolubilized antibodies. When CD22 ligation by a soluble antibody occurs, the interaction with other molecules closely located on the same membrane micro domain (CD32B, CD72, and HLA Class I, among others) may induce humoral as well as a dendritic cell-mediated responses. When CD22 is bound by the insolubilized antibody, this lead to an increase of antibody-mediated signals on the FcR+ cells. A consequence is that CD22 might be involved in the modulation of a humoral response by lymphocytes and dendritic cells.