Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma

Our plain-English summary of Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma, by P.L. Chia, S. Parakh, M.S. Tsao, et al (Pharmaceuticals, 2020).

The study

• Authors: P.L. Chia, S. Parakh, M.S. Tsao, N.A. Pham, H.K. Gan, D. Cao, I.J.G. Burvenich, A. Rigopoulos, E.B. Reilly, T. John, A.M. Scott
• Journal: Pharmaceuticals
• Published: 2020;13(10)
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a 89Zr-labeled immunoconjugate-ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using 89Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.

In plain English

This laboratory and mouse study tested experimental antibody-drug conjugates against malignant mesothelioma. The drugs use an antibody (mAb806) that binds a part of the EGFR protein exposed on tumor cells. The study did not examine asbestos exposure, and no patients were treated. All four mesothelioma cell lines stained strongly for EGFR; three showed the mAb806 target, but NCIH-2452 did not. In mice carrying MSTO-211H tumors, ABT-414 and ABBV-221 slowed tumor growth compared with a control drug. Day-21 tumor sizes were similar to cisplatin's (p = 0.46), but median survival was 81 and 100 days, versus 48 for control and 54 for cisplatin. In mice carrying a patient-derived epithelioid tumor (14R091), ABBV-322 gave smaller tumors than the control (96 versus 183 mm3) and longer median survival (150 versus 122 days). In a patient-derived biphasic tumor lacking the mAb806 target (MPM36), ABBV-322 had no significant effect. A radioactively labeled form of the antibody showed tumors on PET scans in two mice with target-positive MSTO-211H tumors. The authors concluded that targeting EGFR with such drugs is a valid strategy deserving further study.

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: Preclinical laboratory study: cell-line experiments, mouse tumor experiments (cell-line xenografts and patient-derived xenografts), and mouse PET imaging
• Who was studied: The study used four mesothelioma cell lines (MSTO-211H, NCIH-28, NCIH-2052, NCIH-2452). It also used female NSG and BALB/c nu/nu mice carrying either MSTO-211H tumors (n = 10 per group) or patient-derived mesothelioma tumors: 14R091, epithelioid (n = 5 per group), and MPM36, biphasic. The patient-derived models came from Princess Margaret Hospital, Toronto. The animal work was done in Melbourne, Australia.
• Exposure: No asbestos exposure was studied. The treatments tested were the mAb806-based drugs ABT-414, ABBV-221 and ABBV-322, compared with control drugs, cetuximab and cisplatin. In the MSTO-211H study the drugs were given at 3 mg/kg every 4 days. In the patient-derived tumor studies, ABBV-322 or the control was given at 0.03 mg/kg every 4 days, for 12 treatments.
• Main results:
  • EGFR staining (H scores) was 150, 210, 125 and 230 in MSTO-211H, NCIH-28, NCIH-2052 and NCIH-2452 respectively
  • mAb806 target staining (H scores) was 120, 175, 80 and below 5 in MSTO-211H, NCIH-28, NCIH-2052 and NCIH-2452 respectively
  • In cell cultures, ABT-414 and ABBV-221 inhibited growth significantly more than cetuximab (p less than 0.05) and about as well as cisplatin
  • In MSTO-211H mice at day 21, mean tumor volumes were 91.3 mm3 (ABT-414), 61.7 mm3 (ABBV-221) and 70.5 mm3 (cisplatin), with no significant difference (p = 0.46)
  • In MSTO-211H mice, median survival was 81 days with ABT-414 and 100 days with ABBV-221, against 48 days with the control drug and 54 days with cisplatin
  • In 14R091 patient-derived tumor mice at day 27, average tumor volume was 96 mm3 (plus or minus 11) with ABBV-322 against 183 mm3 (plus or minus 22) with the control (p = 0.016)
  • In 14R091 mice, median survival was 150 days with ABBV-322 against 122 days with the control (p = 0.018)
  • In the MPM36 patient-derived tumor, which lacked the mAb806 target, ABBV-322 produced no significant growth inhibition or survival difference compared with the control
  • In mice with mAb806-target-positive MSTO-211H tumors, the radiolabeled antibody (89Zr-ch806) reached a tumor uptake on day 7 that the article prints as 7.02 + 2.18 percent of injected dose per gram of tissue. PET imaging was performed in two animals.
• The authors' conclusion: The authors concluded that targeting EGFR in malignant mesothelioma with these specific antibody-drug conjugates is a valid therapeutic strategy. They also concluded that the findings support further study of mAb806 target expression as a predictive biomarker.
• Limitations the authors state:
  • Patient-derived tumor models are harder to develop and often produce tumors of uneven sizes, which makes them harder to control in treatment experiments
  • Tumors were grown under the skin rather than in the chest (orthotopic models), because orthotopic models are technically difficult in mesothelioma
  • Other targeted therapies that looked promising in preclinical mesothelioma studies did not later show clinical efficacy

Topics

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

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