Tumor-Shed Antigen Affects Antibody Tumor Targeting: Comparison of Two 89Zr-Labeled Antibodies Directed against Shed or Nonshed Antigens

Our plain-English summary of Tumor-Shed Antigen Affects Antibody Tumor Targeting: Comparison of Two 89Zr-Labeled Antibodies Directed against Shed or Nonshed Antigens, by J.H. Lee, H. Kim, Z. Yao, et al (Contrast Media & Molecular Imaging, 2018).

The study

• Authors: J.H. Lee, H. Kim, Z. Yao, L.P. Szajek, L. Grasso, I. Kim, C.H. Paik
• Journal: Contrast Media & Molecular Imaging
• Published: 2018;2018:2461257
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We investigated the effect of shed antigen mesothelin on the tumor uptake of amatuximab, a therapeutic anti-mesothelin mAb clinically tested in mesothelioma patients. The B3 mAb targeting a nonshed antigen was also analyzed for comparison. The mouse model implanted with A431/H9 tumor, which expresses both shed mesothelin and nonshed Lewis-Y antigen, provided an ideal system to compare the biodistribution and PET imaging profiles of the two mAbs. Our study demonstrated that the tumor and organ uptakes of 89Zr-B3 were dose-independent when 3 doses, 2, 15, and 60 μg B3, were compared at 24 h after injection. In contrast, tumor and organ uptakes of 89Zr-amatuximab were dose-dependent, whereby a high dose (60 μg) was needed to achieve tumor targeting comparable to the low dose (2 μg) of 89Zr-B3, suggesting that shed mesothelin may affect amatuximab tumor targeting as well as serum half-life. The autoradiography analysis showed that the distribution of 89Zr-B3 was nonuniform with the radioactivity primarily localized at the tumor periphery independent of the B3 dose. However, the autoradiography analysis for 89Zr-amatuximab showed dose-dependent distribution profiles of the radiolabel; at 10 μg dose, the radiolabel penetrated toward the tumor core with its activity comparable to that at the tumor periphery, whereas at 60 μg dose, the distribution profile became similar to those of 89Zr-B3. These results suggest that shed antigen in blood may act as a decoy requiring higher doses of mAb to improve serum half-life as well as tumor targeting. Systemic mAb concentration should be at a severalfold molar excess to the shed Ag in blood to overcome the hepatic processing of mAb-Ag complexes. On the other hand, mAb concentration should remain lower than the shed Ag concentration in the tumor ECS to maximize tumor penetration by passing binding site barriers.

In plain English

This was an experiment in mice, not a study of people or asbestos exposure. The authors compared two antibodies labeled with radioactive zirconium-89. Amatuximab, tested in mesothelioma patients, targets mesothelin, a protein tumor cells shed into the blood. B3 targets Lewis-Y, a carbohydrate antigen that is not shed from the tumor surface. The mice carried A431/H9 tumors, which come from an epidermoid carcinoma cell line engineered to make human mesothelin. Mice received different doses, and uptake was measured by organ counts at 24 hours, PET scans up to 48 hours, and tumor-slice imaging. Amatuximab uptake in tumor, blood, liver and spleen depended on the dose, while B3 uptake did not. On PET at 48 hours, amatuximab tumor uptake was 7.74 ± 1.22 percent of injected dose per gram at 10 micrograms and 22.90 ± 6.18 at 60 micrograms. The authors concluded that shed antigen in the blood may act as a decoy, so antibody in the blood should be at a severalfold molar excess over shed antigen. They noted that other shed antigens might behave differently.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (biodistribution, PET imaging and autoradiography in tumor-bearing mice)
• Who was studied: Nude mice implanted with A431/H9 tumors (an epidermoid carcinoma cell line transfected with human mesothelin, also expressing Lewis-Y); 4 to 5 mice per group for biodistribution and 5 mice for PET imaging
• Exposure: Zirconium-89-labeled anti-mesothelin antibody amatuximab (2, 10 or 60 micrograms) and anti-Lewis-Y antibody B3 (2, 15 or 60 micrograms), injected intravenously; no asbestos or fiber exposure was studied
• Main results:
  • In biodistribution at 24 hours, amatuximab uptake in tumor, liver, spleen and blood correlated with dose, whereas B3 uptake in these organs was dose-independent
  • On PET, amatuximab tumor uptake (percent injected dose per gram) at the 10 microgram dose was 7.46 ± 1.26, 9.88 ± 1.25 and 7.74 ± 1.22 at 3, 24 and 48 hours
  • On PET, amatuximab tumor uptake at the 60 microgram dose was 22.90 ± 6.18 percent injected dose per gram at 48 hours
  • For amatuximab, the tumor-to-liver ratio on PET was above 1 at 24 and 48 hours with the 60 microgram dose but below 1 with the 10 microgram dose
  • B3 PET images showed no significant dose effects on uptake and clearance from tumor, blood and liver
  • In tumor slices, amatuximab at 10 micrograms had similar radioactivity at the tumor core and periphery; at 60 micrograms uptake increased at the periphery but not the center. B3 uptake peaked at the periphery at either dose
• The authors' conclusion: The authors concluded that shed antigen in blood may act as a decoy, and that systemic antibody concentration should be at a severalfold molar excess over shed antigen in the blood, while staying below the shed antigen concentration in the tumor's extracellular space to maximize tumor penetration
• Limitations the authors state:
  • Other shed antigens with a different binding epitope or affinity might show different effects, so further study is needed before generalizing

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelioma.

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