A preclinical evaluation of mesothelin-specific tumor imaging using 111In-CHX-A”-MORAb-009, a chimeric monoclonal antibody

Objectives Mesothelin is overexpressed in mesothelioma, pancreatic, non-small cell lung carcinoma and ovarian cancers. Three mesothelin-targeting therapeutic agents, including the chimeric monoclonal antibody MORAb-009, are in clinical trials for the treatment of these cancers. We examined the use of 111In-labeled CHX-A”-MORAb-009 to non-invasively evaluate mesothelin expression.

Methods Immunoreactivity of CHX-A”-MORAb-009 was evaluated by cell radioimmunoassays. Mesothelin-expressing (H2052 and A431/K5) and non-expressing (A431) tumors were grown s.c. in athymic mice for 10-12 d after which 125I-MORAb-009 and 111In-CHX-A”-MORAb-009 using different total MORAb-009 protein doses (1-100 µg) were administered iv. The mice were imaged with the nanoSPECT and an in-house built flat dual gamma camera. 18FLT PET images were also acquired. Biodistribution were correlated with the acquired images.

Results Cell binding confirmed CHX-A”-MORAb-009 retained the immunoreactivity. Tumor uptake was >15% ID/g (48 h) for A431/K5 and H2052 using 111In-CHX-A”-MORAb-009 at low protein dose (~1 µg), however, a high liver and spleen uptake (>30% ID/g) was observed for A431/K5 due to higher antigen shedding than H2052. By increasing the protein dose (30-100 µg), accumulation of 111In-CHX-A”-MORAb-009 shifted from the liver/spleen (<20% ID/g) to the tumor (>25 % ID/g). Tumor uptake for the A431 (negative) was <10% ID/g. 125I-MORAb-009 remained low (<10% ID/gm) for both A431/K5 and H2052 throughout the study due to a fast internalization and subsequent dehalogenation. FLT uptake was observed regardless of their mesothelin expression.

Conclusions We demonstrated the use of 111In-CHX-A”-MORAb-009 with an optimal protein dose to evaluate mesothelin expression and facilitate mesothelin-targeted therapies