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

Abstract

See the associated article on page 902. Monocl onal 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.

Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody

“…PET imaging with a 89 Zr-labeled mAb may be used to gain better insight into the in vivo behavior of antibodies. 1,12,13 For any immunotherapeutic antibody evaluation, the first and foremost issue is to assess target saturation, which is helpful for effective therapy dose selection. In this study, dose escalation PET imaging was performed, and the dosedependent target engagement was first evaluated for a BsAb.…”

“…A key point of the modified Patlak model proposed is that a strong correlation was observed between the in vivo heart uptake from PET imaging and the ex vivo serum concentration analyzed by ELISA. Additionally, the AUC was fitted by the corresponding whole blood (for radio detector and PET imaging) or serum concentration (ELISA) using equation (1). According to equation 1to (4) of the target engagement analysis, we inferred that under the condition that the radioactive component does not affect the blood concentration or can be calibrated, this noninvasive-modified Patlak model might be constrained to biologics with a similar convenient expression pattern.…”

“…Therefore, using the maximum tolerated dose method applied to small-molecule cytotoxic agents is not suitable for antibody drugs. 1 Currently, the biologically effective dose (BED) concept is used for the selection of antibody dosing in clinical settings. Target engagement assessment is an important parameter for optimizing the BED of antibodies and antibody conjugates, and it can be used to construct pharmacokinetic/pharmacodynamic (PK/PD) models bridging animal and human testing.…”

“…Target engagement assessment is an important parameter for optimizing the BED of antibodies and antibody conjugates, and it can be used to construct pharmacokinetic/pharmacodynamic (PK/PD) models bridging animal and human testing. [1][2][3][4][5] Flow cytometry, [5][6][7][8] enzyme-linked immunosorbent assays (ELISAs), 9 and mass spectrometry 10 are commonly employed to measure the target saturation of monoclonal antibody (mAb) binding to the receptors of circulating blood cells, and immunohistochemistry (IHC) is usually used to assess the selective localization of target proteins in tissue specimens. 8,11 Studies have shown that molecular imaging can be used to assess target engagement.…”

“…8,15 Second, it can provide real-time and accurate systemic antibody IHC imaging of the whole body simultaneously, not only for all tumor lesions and their metastases but also for normal tissues, such as the spleen, which is an immune organ that is expected to predict the safety of antibody immunotherapy. 17 In addition to its use in PK investigations of mAbs, 18 including BsAbs 19,20 and antibody-drug conjugates (ADCs), 21 recent studies 1,4,13 have shown that the target engagement for mAbs can be assessed by PET. The assessment of BsAbs, however, is more urgent and difficult than that for canonical (i.e., monospecific) mAbs.…”