Radretumab Radioimmunotherapy in Patients with Brain Metastasis: A 124I-L19SIP Dosimetric PET Study

Abstract

Radioimmunotherapy (RIT) with 131 I-labeled L19SIP (radretumab; a small immunoprotein format antibody directed against the ED-B domain of fibronectin; $80 kDa molecular weight) has been investigated in several clinical trials. Here, we describe the use of immuno-PET imaging with iodine-124 ( 124 I)-labeled L19SIP to predict doses delivered to tumor lesions and healthy organs by a subsequent radretumab RIT in patients with brain metastases from solid cancer. Bone marrow doses were evaluated both during the diagnostic phase and posttherapy, measuring activities in blood (germanium detector) and whole body (lanthanum bromide detector). Expected doses for radretumab administration (4,107 MBq/m 2 ) were calculated from data obtained after administration of an average of 167 MBq 124 I-L19SIP to 6 patients. To assess lesion average doses, the positron emission tomography (PET) scanner was calibrated for the use of 124 I with an International Electrotechnical Commission (IEC) Body Phantom and recovery coefficients were calculated. The average dose to bone red marrow was 0.21 Gy/GBq, with high correlation between provisional and actual posttherapy doses. Although the fraction of injected activity in normal organs was similar in different patients, the antibody uptake in the neoplastic lesions varied by as much as a factor of 60. Immuno-PET with 124 I-labeled L19SIP offers significant advantages over conventional 131 I imaging, in particular accuracy of dosimetric results. Furthermore, the study indicates that antibody uptake can be highly variable even in different lesions of the same patient and that immuno-PET procedures may guide product development with armed antibodies. Cancer Immunol Res; 1(2); 134-43. Ó2013 AACR.

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

“…For both compounds, a half-life in PBS > 48 hours was observed. A lower stability was seen in mouse serum, but >70% of both conjugates were intact after 6 hours (i.e., a sufficiently long time, compared to the circulatory half-life of acetazolamide derivatives in blood, which is typically shorter than 15 min) [16]. Mass spectrometric analysis of compound 4a revealed free MMAE as the main release product, while in the degradation profile of compound 5a in mouse serum free PNU-159682 was not identified, probably due to low sensitivity of the mass spectrometer to a such hydrophobic moiety.…”

“…Unfortunately, such a high therapeutic index is rarely observed in the clinic, suggesting that the tumor targeting properties of the antibody, the drug release process and/or the intrinsic sensitivity of tumor cells may be dramatically different in preclinical models and in cancer patients. Nuclear medicine studies with radiolabeled antibody preparations have previously shown that lower tumor:organ ratios are often observed in humans compared to tumor-bearing mice, possibly reflecting differences in antigen abundance and vascular permeability [16,17]. SMDCs may represent an attractive alternative to ADC products, as smaller pharmaceuticals extravasate more rapidly and diffuse more homogenously within the neoplastic mass [2,[18][19][20][21][22].…”

“…Unlike antibodies (which can easily be raised against the majority of target proteins of interest), it is not always easy to generate high-affinity small molecule ligands to tumor-associated antigens. However, excellent tumor-targeting results have been reported for folate analogues targeting folate-receptor positive tumors [23,24], substituted urea derivatives targeting prostate-specific membrane antigen [25], somatostatin antagonists targeting the somatostatin receptor [26] and for carbonic anhydrase IX (CAIX) ligands [16][17][18]27].…”

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

“…5A) should provide a rational basis for the comparison of therapeutic efficacy in different models of cancer. Accurate dosimetric studies of tumor-targeting performance in patients, which are possible thanks to advances in antibody radiolabeling procedures (30) and to the implementation of immuno-PET procedures (15,42), should allow a direct comparison of clinical data with biodistribution results in mice, facilitating product development and translational research.…”

“…Immunofluorescence and microautoradiographic analysis, following intravenous administration of the L19 and F8 antibodies to tumor-bearing mice, confirmed that the antibodies efficiently and preferentially localized to tumor blood vessels in vivo. Quantitative biodistribution studies of antibody uptake are available in tumor-bearing mice (9,12,13) and in patients with cancer (14,15).…”