Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody

Background: Mesothelin (MSLN) is a tumor differentiation antigen that is highly expressed by cells of many epithelial tumors, with limited expression in normal human tissues. Our understanding of therapeutic antibodies targeting MSLN might benefit from immunoPET imaging of antibody uptake. We developed and preclinically validated an 89Zr labeled anti-MSLN antibody (“89Zr-AMA”) for this noninvasive imaging of tumor and normal organ uptake. Methods: 89Zr was attached to an anti-MSLN humanized IgG1 monoclonal antibody derivatized with the bifunctional chelator reagent N-succinyldesferrioxamine-B-tetrafluorphenol. The 89Zr-AMA was characterized in terms of conjugation ratio, aggregation, radiochemical purity, stability, and immunoreactivity. Two human MSLN-expressing pancreatic tumor cell lines, HPAC and CAPAN-2, were used for xenograft studies in mice. Tumor uptake and organ distribution of 89Zr-AMA were studied in the HPAC line at three protein doses (10, 25 and 100 μg) labeled with 1 MBq 89Zr and results were compared with nonspecific 111In-IgG. After dose-finding, CAPAN-2 and HPAC tumor xenograft-bearing mice were scanned with μPET at 1, 3, and 6 days after tracer injection of the optimal AMA dose labeled with 5 MBq 89Zr, followed by ex vivo biodistribution at day 6. Tracer uptake was quantified and expressed as mean standardized uptake values (SUVmean). Results: 89Zr-AMA formed with high specific activity (> 500 MBq/mg), high yield (> 90% without further purification), and high purity (> 95% determined by SE-HPLC analysis). In vitro validation of 89Zr-AMA showed a fully preserved immunoreactivity with a long (> 1 week) stability in 0.9% NaCl. Biodistribution analyses of the dose-finding groups revealed a dose-dependent 89Zr-AMA tumor uptake, with the highest fractional tumor uptake in the 10 μg dose group, 14.2 %ID/g on day 6. Tumor uptake of the non-specific control antibody, 111In-IgG, was lower than that of the 89Zr-AMA (P <0.05, paired t test). Day 6 89Zr-AMA biodistribution data from the animals that underwent μPET showed ex vivo tumor uptake of 12.0 %ID/g in HPAC and 11.8 %ID/g in CAPAN-2 tumors and 4.6 and 4.4 %ID/g in blood. Uptake of the nonspecific control 111In-IgG was 5.7 %ID/g for HPAC and 3.6 %ID/g for CAPAN-2 tumors, and 10.0 and 7.5 %ID/g for their respective blood pools. MicroPET imaging was consistent with the biodistribution data. 89Zr-AMA showed a progressive increase in tumor uptake over time, whereas the activity in the blood pool decreased; in liver, spleen and kidney it remained stable. Conclusion: 89Zr-AMA tumor uptake is antigen-specific in MSLN-expressing tumors. This tracer can be translated to the clinic for serial non-invasive PET imaging

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer

Phase I Study of DMOT4039A, an Antibody-Drug Conjugate Targeting Mesothelin, in Patients with Unresectable Pancreatic or Platinum-Resistant Ovarian Cancer

DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2-2.8 mg/kg; q3w) or weekly (0.8-1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer. (C) 2016 AACR