Advances in immuno-positron emission tomography: antibodies for molecular imaging in oncology

Abstract

Identification of cancer cell-surface biomarkers and advances in antibody engineering have led to a sharp increase in the development of therapeutic antibodies. These same advances have led to a new generation of radiolabeled antibodies and antibody fragments that can be used as cancer-specific imaging agents, allowing quantitative imaging of cell-surface protein expression in vivo. Immuno-positron emission tomography (immunoPET) imaging with intact antibodies has shown success clinically in diagnosing and staging cancer. Engineered antibody fragments, such as diabodies, minibodies, and single-chain Fv (scFv) -Fc, have been successfully employed for immunoPET imaging of cancer cell-surface biomarkers in preclinical models and are poised to bring same-day imaging into clinical development. ImmunoPET can potentially provide a noninvasive approach for obtaining target-specific information useful for titrating doses for radioimmunotherapy, for patient risk stratification and selection of targeted therapies, for evaluating response to therapy, and for predicting adverse effects, thus contributing to the ongoing development of personalized cancer treatment.

Fig 1.

Zirconium-89–trastuzumab localizes to human epidermal growth factor receptor 2–expressing tumors 5 days postinjection. (A) Patient with liver and bone metastases, and (B, C) two patients with multiple bone metastases. (B) One patient shows high cardiac uptake, which may suggest she is at risk for adverse cardiac events with trastuzumab therapy. Reprinted with permission.

Fig 2.

The half-lives of immuno–positron emission tomography imaging agents can be modified by deleting constant domains to create fragments of varying size (single-chain Fv [scFv] –Fc, minibody, and diabody) and/or by mutations modifying their interactions with the FcRn antibody rescue receptor (scFv-Fc H310A/H435Q double mutant [DM]). Optimal imaging time points have high tumor uptake with low blood activity. For intact antibodies, imaging at 96 to 168 hours provides optimal contrast. Antibody fragments such as scFv-Fc wild type (WT; 72 to 120 hours), scFv-Fc DM (12 to 48 hours), minibodies (8 to 48 hours), and diabodies (4 to 8 hours) are capable of obtaining high-contrast images at earlier time points.

Fig 3.

Micro–positron emission tomography (PET)/computed tomography imaging of mice bearing prostate stem-cell antigen (PSCA) –expressing LAPC-9 prostate cancer xenografts shows various anti-PSCA antibody fragments can target and image PSCA expression in vivo. (A, B) Imaging with intact antibodies or single-chain Fv–Fc (scFV-Fc) wild type (WT) requires waiting 5 to 7 days after injection before imaging. (C, D) scFv-Fc H310A/H435Q double mutant (DM) and minibodies can be imaged the day after injection. (E) Diabodies diffuse into tumors and clear quickly enough to allow for microPET imaging the same day with short-lived radioisotopes such as fluorine-18 (¹⁸F). (C, D) Iodine-124 (¹²⁴I)–labeled probes show bladder signal at early time points because of clearance of ¹²⁴I-iodotyrosine and ¹²⁴I-iodide produced by antibody catabolization. (E) ¹⁸F-fluorobenzyl–labeled probes often show gallbladder and cecum signal because of excretion of radiolabeled metabolites in bile. All microPET images were scaled individually to best show tumor targeting.

Fig 4.

Expression of prostate-specific membrane antigen (PSMA) in prostate cancer is regulated by androgens. (A) Testosterone supplementation decreases PSMA expression and uptake of a copper-64 (⁶⁴Cu) –DOTA–labeled anti-PSMA intact antibody in mice bearing bilateral CWR22rv1 prostate cancer xenografts. (B) Androgen receptor inhibition with MDV3100, on the other hand, increases PSMA expression and uptake of ⁶⁴Cu-DOTA–labeled anti-PSMA in mice bearing bilateral LNCaP androgen receptor prostate cancer xenografts. Reprinted with permission. Trans, transverse.