Temporal Modulation of HER2 Membrane Availability Increases Pertuzumab Uptake and Pretargeted Molecular Imaging of Gastric Tumors

Harnessing 64 Cu/ 67 Cu for a theranostic approach to pretargeted radioimmunotherapy

“…Broadly speaking, this methodology consists of four steps: 1) the administration of a monoclonal antibody (mAb)-TCO immunoconjugate; 2) an interval period during which the antibody accumulates at the tumor and clears from the blood; 3) the injection of a small molecule Tz-based radioligand; and 4) the in vivo click ligation between two components, followed by the rapid clearance of any excess radioligand. This strategy has proven highly effective for pretargeted PET imaging (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49) as well as pretargeted radioimmunotherapy (PRIT) using beta-emitting ( 177 Lu) and alpha-emitting ( 225 Ac) radionuclides (50)(51)(52)(53)(54)(55). Yet as the field stands poised to make the jump from the laboratory to the clinic, it stands to reason that the development of a theranostic approach to Tz/TCO pretargeting could prove instrumental in ensuring the future success of this modality.…”

Design and preclinical evaluation of nanostars for the passive pretargeting of tumor tissue

“…After a one-week acclimatization period, CT26 cells (1 × 10 5 cells) in 150 μL 1:1 growth media/Matrigel® (BD Biosciences, San Jose, CA) were subcutaneously injected into the flank or shoulder using a sterile syringe equipped with a 28gauge needle. Tumor volume V was calculated according to the formula V = (4π/3) × (a/2) 2 × (b/2), in which a and b were defined as the longest tumor axis and its perpendicular axis, respectively, as estimated by Vernier caliper measurements [36]. When tumor volumes reached 100-250 mm 3 (2-3 weeks post-injection), mice were injected with 150 μg TCOfunctionalized nanostars in 130-150 μL 5% DMSO.…”

Antibody-Targeted Imaging of Gastric Cancer

“…ImmunoPET and immunoSPECT have been used for the non-invasive imaging of gastric cancer in both preclinical and clinical studies. The first section of the review will discuss the use of immunoPET in GC targeting the antigens carcinoma-associated antigen (MG7) [ 14 ], programmed death-1 (PD-1) [ 16 ], cadherin-17 (CDH17) [ 15 ], human epidermal growth factor receptors 2 and 3 (HER2 [ 5 , 9 , 21 , 22 , 23 , 24 ] and HER3 [ 12 ]), hepatocyte growth factor (HGF [ 11 ]), and the mesenchymal-epithelial transition factor (MET) [ 10 ]. As shown in Table 1 , FDA-approved or newly developed antibodies targeting membrane antigens were radiolabeled with gallium-68 ( 68 Ga), technetium-99m ( 99m Tc), indium-111 ( 111 In), copper-64 ( 64 Cu), zirconium-89 ( 89 Zr), and bromine-76 ( 76 Br) and used for PET or SPECT imaging of gastric tumors.…”

“…Indeed, HER2 heterogeneity exists not only between primary tumors and metastases, but also in the primary tumor alone, and within the same lesion before and after treatment [ 6 ]. In this context, PET and SPECT using radiolabeled anti-HER2 antibodies have demonstrated great potential to non-invasively image and monitor HER2 expression in both preclinical models and patients with GC [ 5 , 9 , 21 , 22 , 23 , 24 ].…”

“…HER2 internalization reduces HER2 availability at the cell membrane and, consequently, decreases anti-HER2 antibody-tumor binding. Pereira et al used cholesterol-depleting drugs in an attempt to temporarily stabilize HER2 at the cell membrane and enhance the ability of the 89 Zr-labeled anti-HER2 antibodies trastuzumab [ 23 ] and pertuzumab [ 24 ] to bind to HER2-expressing gastric xenografts.…”