CD74 is an attractive target for
antibody-drug conjugates (ADC), because it internalizes and recycles after antibody binding. CD74 mostly is associated with hematologic
tumors but is expressed also in solid
cancers. Therefore, ADCs of the humanized anti-CD74 antibody,
milatuzumab, were examined for the
therapy of CD74-expressing solid
tumors.
Milatuzumab-
doxorubicin and two milatuzumab-SN-38 conjugates with cleavable linkers, differing in their stability in serum and how they release
SN-38 in the lysosome, were prepared. CD74 expression was determined by flow cytometry and immunohistology. In vitro cytotoxicity and in vivo therapeutic studies were conducted in the human
cancer cell lines A-375 (
melanoma), HuH-7 and Hep-G2 (
hepatoma), Capan-1 (pancreatic), NCI-N87 (gastric), and Raji
Burkitt lymphoma. The milatuzumab-SN-38 ADC was compared with
SN-38 ADCs prepared with anti-Trop-2 and anti-CEACAM6
antibodies in xenografts expressing their target
antigens.
Milatuzumab-
doxorubicin was most effective in the
lymphoma model, whereas in A-375 and Capan-1 solid
tumors, only milatuzumab-SN-38 showed a therapeutic benefit. Despite much lower surface expression of CD74 than Trop-2 or CEACAM6, milatuzumab-SN-38 had similar efficacy in Capan-1 as anti-Trop-2-SN-38, but in NCI-N87, anti-CEACAM6 and anti-Trop-2 conjugates were superior. Studies in two
hepatoma lines at a single dose level showed significant benefit over saline controls but not against an irrelevant
immunoglobulin G conjugate. CD74 is a suitable target for ADCs in some solid
tumor xenografts, with efficacy largely influenced by uniformity of CD74 expression and with
SN-38 conjugates providing the best therapeutic responses;
SN-38 conjugates were preferable in solid
cancers, whereas
doxorubicin ADC was better in
lymphoma tested.