89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Abstract

# These authors contributed equally to this work. AbstractPurpose-We evaluated biodistribution and tumor targeting of 89 Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental design-20 patients with histologically confirmed HER3-expressing tumors received 89 Zr-lumretuzumab and underwent Positron Emission Tomography (PET). In Part A, 89 Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab and scans were performed 2, 4 and 7 days postinjection to determine optimal imaging conditions. In Part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results-Optimal PET conditions were found to be 4 and 7 days after administration of 89 Zrlumretuzumab with 100 mg unlabeled lumretuzumab. At baseline using 100 mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days postinjection. SUVmean for normal blood, liver, lung and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n=7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5) and 24.6% (±20.9) at PD-active doses of 400, 800 and 1600 mg, respectively, when compared to baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400 mg lumretuzumab.Conclusions-PET imaging showed biodistribution and tumor specific 89 Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89 Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses.

Molecular Imaging in Cancer Drug Development

“…In 4 of 5 tumors, tracer uptake corresponding to contrast-enhanced areas on MRI was seen, as is highly suggestive of leakage in the blood-brain barrier. In another study, with trastuzumab and lumretuzumab, specific tracer uptake in multiple brain metastases was seen (31,34). Although clinical evidence is scarce, first results demonstrate the potential of molecular imaging for studying CNS penetration of mAbs.…”

“…In a study with 89 Zr-lumretuzumab targeting human epidermal growth factor receptor 3, increasing doses of lumretuzumab did not lead to a plateau of tumor 89 Zr-lumretuzumab uptake, possibly because of highly dynamic receptor expression, reflecting the difficulty in defining the maximum required mAb dose in the clinic (34).…”

Benefit of Later-Time-Point PET Imaging of HER3 Expression Using Optimized Radiocobalt-Labeled Affibody Molecules

“…For example, the anti-HER3 antibody 89 Zr-lumretuzumab provided good imaging contrast 4-7 days after injection and enabled quantification of the uptake in HER3 positive tumors in a small clinical study. However, only in non-hepatic cancer lesions [13]. A major drawback of radiolabeled antibodies for imaging is the long residence time in blood and their hepatobiliary elimination pathway.…”

In Vivo Molecular Imaging for Biomedical Analysis and Therapies

“…3,31 For PET imaging, 89 Zr (halflife: 78.4 h) can be used for imaging with intact antibodies. 32,33 Antibody fragments are used for specific imaging over short time periods since the blood half-lives are shorter for the fragments. 34 Shorter half-life radionuclides are used for this purpose, such as 64 Cu (half-life: 12.7 h) for PET 35,36 and 99m Tc (half-life: 6.02 h) for SPECT.…”