Tyrosine Kinase Inhibitor Sorafenib Decreases ¹¹¹In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti-carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximabbased therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of 111 In-labeled girentuximab. Methods: 111 In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of 111 In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single 111 In-girentuximab injection and scintigraphy without any treatment. Distribution of 111 In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue. Results: Treatment with sorafenib resulted in a marked decrease of 111 In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, 238.4%; range, 19.1% to 279.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients. Conclusion: Treatment with sorafenib resulted in a treatment duration-dependent significantly decreased uptake of 111 In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.

Esterase activity of carbonic anhydrases serves as surrogate for selecting antibodies blocking hydratase activity

“…One CA9-specific mAb (G250, Girentuximab) has entered late-stage clinical development 16 . Unfortunately, the anti-tumor effect of Girentuximab in patients with renal cancer was limited, and no clinical activity was observed in a recently published large randomized trial [16][17][18][19] . The lack of efficacy was partially ascribed to the inability of Girentuximab to block CA9 enzymatic activity 16 .…”

Antibody–Drug Conjugates and Small Molecule–Drug Conjugates: Opportunities and Challenges for the Development of Selective Anticancer Cytotoxic Agents

“…Few monoclonal antibodies have been studied with nuclear medicine procedures and adequate dosimetric analyses in a sufficiently large number of patients. [10][11][12][13][14][15][16][17][18][19] In those studies, a large variability in tumor uptake, from patient to patient and from lesion to lesion, was observed. Antibodies which display tumor:organ and tumor:blood ratios > 5:1, 24…”

“…21,23,24 However, in humans, typically more than 99% of the antibody administered, does not reach the tumor. [10][11][12][13][14][15][16][17][18][19] The persistent high-levels of drug-conjugate in blood may be responsible for undesired toxicities as a consequence of both premature, and undesired drug release in off-target organs (e.g. endothelium, liver; Figure 2b).…”

Evaluation of Nonpeptidic Ligand Conjugates for SPECT Imaging of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers

“…For example, CA IX-specific peptide and small molecule ligands have been used to image moue xenograft models of colon 47–52 , renal 53 and cervical cancers 51 . CA IX-specific antibodies have also been exploited to image mouse cancer xenograft models of the kidney 54–57 , head & neck 58 , colon 59,60 and cervix 61 in addition to human patients with clear cell renal carcinomas 62–66 . However, small molecule conjugates have primarily used only PET 49,50 or fluorescence 51–53 imaging modalities to visualize hypoxic tumors.…”