Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate

Our plain-English summary of Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate, by M.G. Anderson, H.D. Falls, M.J. Mitten, et al (Molecular Cancer Therapeutics, 2020).

The study

• Authors: M.G. Anderson, H.D. Falls, M.J. Mitten, A. Oleksijew, K.S. Vaidya, E.R. Boghaert, W. Gao, J.P. Palma, D. Cao, P.L. Chia, T. John, H.K. Gan, A.M. Scott, E.B. Reilly
• Journal: Molecular Cancer Therapeutics
• Published: 2020;19(10):2117-2125
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or amplification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and in vivo studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.

©2020 American Association for Cancer Research.

In plain English

This laboratory and animal study tested ABBV-321 (serclutamab talirine), an experimental drug joining an antibody against EGFR, a protein on many tumor cells, to a potent cell-killing chemical (a PBD dimer). It did not study asbestos or asbestos exposure. The authors tested it on glioblastoma (brain cancer) and colorectal cancer cell lines and on human tumors grown in mice. These included 18 lung and head and neck tumor models from patients and one malignant mesothelioma model from a patient. They also measured the drug in monkey blood. In many cell lines and mouse tumors, ABBV-321 worked at lower doses than an earlier related drug, ABBV-221. In the mesothelioma model, the authors reported significant tumor growth suppression with ABBV-321 compared with a non-targeted control drug or cisplatin chemotherapy. In monkeys, measurable released toxin was not detected in blood. The authors concluded that these preclinical results supported continuing studies in patients with EGFR-positive tumors. They noted that, because the blood-brain barrier hinders large drugs, results in mice with tumors grown in the brain may further support testing for glioblastoma.

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 and animal study of an experimental drug: cell-culture tests, mouse tumor models (cell-line xenografts and patient-derived xenografts), and pharmacokinetics in cynomolgus monkeys
• Who was studied: 16 human brain cancer cell lines and 22 colorectal cancer cell lines (Tables 2 and 3). Mice carrying human glioblastoma, lung, head and neck and colorectal tumors. A panel of 18 patient-derived lung (NSCLC) and head and neck tumor models. One EGFR-positive malignant mesothelioma patient-derived model (PDX #1174) studied at Austin Hospital, Victoria, Australia. Cynomolgus monkeys (number not given).
• Exposure: The experimental antibody-drug conjugate ABBV-321, an EGFR-targeting antibody (AM1) joined to a PBD dimer toxin, compared with related drugs ABBV-221 and depatux-m, non-targeted control conjugates, and, in the mesothelioma model, cisplatin. No asbestos exposure was studied.
• Main results:
  • In the malignant mesothelioma mouse model PDX #1174 (EGFR IHC score 3+), ABBV-321 at 0.15 mg/kg twice weekly for 3 weeks gave significant tumor growth suppression compared with groups treated with a non-targeted ADC or with cisplatin
  • In glioblastoma cell lines without amplified EGFR, ABBV-321 was more potent than ABBV-221, killing many of them at single-digit nanomolar concentrations
  • In all colorectal mouse tumor models tested, ABBV-321 inhibited tumor growth more than ABBV-221 given at ten-fold higher doses
  • Across 18 patient-derived lung and head and neck mouse tumor models, ABBV-321 (0.6 mg/kg) was in most cases significantly more effective than ABBV-221 at a ten-fold higher dose (6 mg/kg)
  • In the GBM1 glioblastoma mouse model, a combination of lower doses of ABBV-321 (0.1 mg/kg) and depatux-m (1.4 mg/kg) inhibited tumor growth, while either drug alone was much less effective
  • In cynomolgus monkeys given 25 to 100 micrograms per kg, quantifiable released PBD toxin was not detected in any dose group (lower limit of quantitation 50 pg/mL)
• The authors' conclusion: The authors concluded that their preclinical results support continuing investigational studies of ABBV-321 in patients with EGFR-positive tumors
• Limitations the authors state:
  • Because an intact blood-brain barrier makes it hard to deliver large-molecule drugs to patients with glioblastoma, the authors said that showing efficacy in models where tumors grow in the brain (orthotopic models) may provide further preclinical validation for this use.
  • In the GBM1 model, the non-targeting PBD dimer control drug also showed activity at higher doses. The authors attributed this to enhanced permeability and retention effects in tumors.

Topics

Medical terms in this study, explained in our Lexicon: EGFR, Malignant Mesothelioma, Clinical Trial.

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