The anti-CD74 humanized monoclonal antibody, milatuzumab, which targets the invariant chain of MHC II complexes, alters B-cell proliferation, migration, and adhesion molecule expression

Surface expression of CD74 on CD27- na？ve and CD27+ memory B cells as well as other peripheral blood mononuclear cells (PBMCs) obtained from normals, including the co-expression of CD44, CXCR4, and the adhesion molecules CD62L, β7-integrin, β1-integrin and CD9 were studied after binding of milatuzumab using multicolor flow cytometry. The influence of the antibody on B-cell proliferation and migration was analyzed in vitro in detail.In addition to monocytes, milatuzumab also specifically bound to human peripheral B cells, with a higher intensity on CD27+ memory versus CD27- na？ve B cells. The antibody reduced B-cell proliferation significantly but moderately, induced enhanced spontaneous and CXCL12-dependent migration together with changes in the expression of adhesion molecules, CD44, β7-integrin and CD62L, mainly of CD27- na？ve B cells. This was independent of macrophage migration-inhibitory factor as a ligand of CD74/CD44 complexes.Milatuzumab leads to modestly reduced proliferation, alterations in migration, and adhesion molecule expression preferentially of CD27- na？ve B cells. It thus may be a candidate antibody for the autoimmune disease therapy by modifying B cell functions.Milatuzumab is a humanized monoclonal antibody (also called hLL1 or IMMU-115) targeting a cell surface-expressed epitope of the molecule CD74 which is expressed on monocytes, macrophages, and B cells but not T cells [1]. Currently, milatuzumab is a candidate immunotherapeutic antibody being studied in multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia (CLL) [1]. B cells of these hematological tumors express the target molecule, CD74, at high levels and internalize it rapidly after milatuzumab binding [2,3]. Consequently, growth inhibition and induction of apoptosis in B-cell lines in the presence of a second cross-linking antibody (for example, Fcγ-specific F(ab)2 fragments to mimic the role of effector cells or cross-linking molecules present in vivo) have been repor