Immuno-PET to Optimize the Dose of Monoclonal Antibodies for Cancer Therapy: How Much Is Enough?

Abstract

Monoclonal antibodies (mAbs) have emerged as one of the most effective and least toxic classes of personalized medicines for cancer (1). These drugs rely on specific recognition of a target receptor for their antitumor effects. The receptors may be expressed on tumor cells or stromal cells (e.g., vascular endothelial cells) or, in the case of immunotherapy, which is aimed at immune checkpoints, by tumor cells or immune effector cells (e.g., T lymphocytes). The clinical development of mAbs follows a pathway applied to all drugs, which includes phase 1 first-in-humans trials to assess safety, phase 2 trials to study effectiveness in a selected patient population, and large, randomized phase 3 trials that lead to regulatory approval and product registration (2). Most first-inhumans trials of mAbs have used a clinical trial design that is common for small-molecule cytotoxic agents, in which escalating doses are administered to patients to identify the maximum tolerated dose (MTD). The recommended dose selected for phase 2 trials is based on the MTD. However, this phase 1 design is inherently flawed for first-in-humans trials of mAbs because it assumes that the effectiveness and normal-tissue toxicity of the drug increases in direct proportion to the administered dose. Because mAbs exhibit saturable binding to their target receptors, one could envision that there is an optimal dose that results in maximum receptor occupancy and yields maximum therapeutic effect. Higher doses would not be expected to provide additional therapeutic benefit but could increase the risk for toxicity. Moreover, in contrast to cytotoxic small-molecule drugs, most mAbs have an excellent safety profile. A survey of 82 first-in-humans trials of mAbs revealed that dose-limiting toxicity was not found in 47 of these studies (57%) and the MTD was reached in only 13 (16%) (3). Instead, the planned maximum administered dose was achieved in all trials, attesting to the excellent safety profile of these drugs. Because the MTD was not identified, in most cases the phase 2 trial dose was based on the maximum administered dose or in some cases on the pharmacokinetic properties of the mAbs to achieve a blood concentration in humans shown to be effective in preclinical studies. In one review of 27 mAbs studied in a total of 60 phase 3 registration trials, the dose examined and eventually approved by the U.S. Food and Drug Administration was actually lower than for phase 2 testing (4). Although these doses of mAbs proved effective, there remains considerable uncertainty about whether or not they are optimal for cancer treatment. Clinical trial designs that attempt to define a biologically effective dose (BED), that is, a dose that is mechanistically optimal, have been proposed as a more rational approach for dosing mAbs for cancer treatment (5). However, identifying the BED requires a biomarker that reports on interactions of mAbs with their target receptors to assess whether the dose is sufficient to yield the desired biologic effects. Ideally, such a biomarker should be readily accessible and not require a tissue biopsy because of the impracticality of sampling all lesions either spatially or temporally in patients. Immuno-PET is a powerful noninvasive tool to assess the tumor uptake of mAbs at any location in the body. Furthermore, immunoPET offers the opportunity to interrogate receptor occupancy in patients treated with mAbs, since PET is quantitative, which could potentially provide a biomarker to select the BED (6). Immuno-PET uses mAbs labeled with positron-emitting radionuclides, most commonly 89Zr (mean b-energy, 0.40 MeV [23%]; physical half-life, 78.4 h). Interestingly, preclinical studies of immuno-PET routinely report the effect of administration of an excess of unlabeled mAbs on the tumor uptake of the radiolabeled mAbs, to confirm the specificity of tumor localization (7). These blocking studies actually reveal receptor occupancy by the unlabeled mAbs, which results in decreased tumor uptake of the radiolabeled mAbs. However, these studies do not identify the optimal dose of the unlabeled mAbs required to block uptake of the radiolabeled mAbs, because they examine only administration of a large excess of the unlabeled mAbs for blocking. To identify the optimal dose would require titration of the effect of increasing doses of unlabeled mAbs on the tumor uptake of the radiolabeled mAbs assessed by immuno-PET. In this issue of The Journal of Nuclear Medicine, Menke-van der Houven van Oordt et al. report an immuno-PET study with 89Zr-labeled GSK2849330 antihuman epidermal growth factor receptor-3 (HER3) mAbs in 6 patients with HER3-positive tumors (8). Tumor and normal-tissue uptake were evaluated, and the effect of therapeutic doses of GSK2849330 mAbs (GlaxoSmithKline) on tumor uptake was assessed as an indicator of receptor occupancy. This report follows an earlier preclinical PET study in which 89ZrGSK2849330 mAbs (0.5 mg/kg; 5 MBq) were administered to Received Apr. 25, 2019; revision accepted May 2, 2019. For correspondence or reprints contact: Raymond M. Reilly, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto Ontario, M5S 3M2 Canada. E-mail: [email protected] Published online May 3, 2019. COPYRIGHT© 2019 by the Society of Nuclear Medicine and Molecular Imaging. DOI: 10.2967/jnumed.119.225854