Abstract #5485: Expression of CD74 in pancreatic and colorectal carcinomas as a basis for milatuzumab immunotherapy (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Background: Monoclonal antibody hLL1 (milatuzumab, Immunomedics, Inc.) is reactive with the transmembrane CD74 invariant chain glycoprotein. The invariant chain associates with the major histocompatibilty class II \#945; and \#946; chains directing the complexes to endosomes and lysosomes. Milatuzumab, when bound to cell-surface CD74 is rapidly internalized along with the complexes. Recently, it has been learned that milatuzumab possesses growth-inhibitory activity. Binding of macrophage migration-inhibitory factor (MIF) to CD74 initiates a signaling cascade resulting in proliferation and survival. This signal cascade is blocked by binding of milatuzumab to cell-surface CD74. Milatuzumab may thus provide a means for targeting tumoricidal agents to the tumor and potentially be employed as an unlabeled MAb to disrupt the MIF initiated survival pathway. The objective of the present study was to evaluate the potential utility of the CD74 target antigen by evaluating the level of expression in several gastrointestinal cancers. Methods: Immunohistochemical (IHC) labeling of colorectal and pancreatic cancers was performed with the hLL1 anti-CD74 MAb and a non-binding, isotype matched MAb as a control. Results: CD74 expression in pancreatic carcinoma was high; of 36 specimens, only 1 was completely negative with 78% of the specimens presenting a mostly intense, diffuse labeling pattern and an additional 19% having a moderate to intense, focal pattern. (Diffuse labeling is when >25% of the carcinoma cells are labeled with the specific MAb and Focal is <25% of the specific cells labeled.) The data suggested a trend towards more intense labeling with lower grade of differentiation; 33%, 64% and 82% of well, moderately, and poorly differentiated specimens, respectively, exhibited intense staining (linear regression, r2=0.977). The majority of the staining was cytoplasmic, although cell-surface staining was also identified. This is in contrast to many of the hematologic cancers (e.g., non Hodgkin lymphoma and multiple myeloma) where a mostly cell-surface labeling was observed. Similar results were seen with colorectal carcinomas. Of 22 colorectal carcinomas, 14 (64%) gave intense, diffuse labeling with an additional 27% having a moderate to intense focal staining pattern. Conclusions: The role of CD74 as a target for immunotherapy of hematologic cancers with milatuzumab has been reviewed by our group (Clin Cancer Res 2007;13:5556s-63s). The current data suggest that CD74 is expressed at high levels within the pancreatic and colorectal carcinomas and that use of milatuzumab may prove effective for immunotherapy of these solid tumors as well. Of particular significance is that, at least with pancreatic carcinomas, the CD74 marker is highly expressed in poorly differentiated carcinomas, a group that tends to be more resistant to current treatment procedures. (Supported in part by USPHS grant CA103985 from the NIH.)

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5485.