Radioimmunotherapy of Solid Tumors by Targeting Extra Domain B Fibronectin: Identification of the Best-Suited Radioimmunoconjugate

Abstract

Purpose: The expression of extra domain B (ED-B) fibronectin is always associated with angiogenic processes and can be exclusively observed in tissues undergoing growth and/or extensive remodeling. Due to this selective expression, ED-B fibronectin is an interesting target for radioimmunotherapy of malignant diseases. The aim of this study was to identify the most appropriate ED-B-targeting radioimmunoconjugate for the therapy of solid tumors. Experimental Design: Three ED-B fibronectin-binding human antibody formats of L19 were investigated: dimeric single-chain Fv (f50 kDa), ''small immunoprotein'' (SIP, f80 kDa), and immunoglobulin G1 (IgG1, f150 kDa). These L19 derivatives were either labeled with I-125 or with In-111 (using MX-diethylenetriaminepentaacetic acid, MX-DTPA). Pharmacokinetics and tumor accumulation of the radiolabeled immunoconjugates were investigated in F9 (murine teratocarcinoma) tumor-bearing mice. Subsequently, dosimetry for the corresponding therapeutic isotopes I-13-1andY-90 was done. After testing the myelotoxicity of I-131-L19-SIP and I-131-L19-IgG1in non-tumor-bearing mice, the therapeutic efficacy of these iodinated antibody formats was finally investigated in F9 tumor-bearing mice. Results: The most favorable therapeutic index was found for I-131-L19-SIP followed by I-131-L19-IgG1. The therapeutic index of all In-111-labeled derivatives was significantly inferior. Considering the bone marrow as the dose-limiting organ, it was calculated that activities of 74 MBq I-131-L19-SIP and 25 MBq I-131-L19-IgG1 could be injected per mouse without causing severe myelotoxicity. The best therapeutic efficacy was observed using I-131-L19-SIP, resulting in significant tumor growth delay and prolonged survival after a single injection. Conclusion: Compared with other L19-based radioimmunoconjugates, I-131-L19-SIP is characterized by superior antitumor efficacy and toxicity profile in the F9 teratocarcinoma animal model. These results indicate that ED-B fibronectin-targeted radioimmunotherapy using I-131-L19-SIP has potential to be applied to treatment of solid cancers.

Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models

“…This ratio was reduced at 72 h, but still remained high at 9.4. In another study comparing the biodistribution of 125 I-L19-SIP and 111 In-L19-SIP in mice bearing the F9 teratocarcinoma tumours, Berndorff et al (2005) found that although tumour uptake was equal with both radionuclides, tumour to non-tumour ratios were higher for the 125 I-labelled antibody.…”

“…It is important to note that, in this study, significant results were obtained with doses lower than that used in other RIT studies with the L19-SIP antibody. Berndorff et al (2005) reported that a single injection of 74 MBq 131 I-L19-SIP to F9 tumour-bearing mice resulted in a 10-day tumour growth delay and a median survival of 22 days; 13 days longer than that of control mice. More recently, Tijink et al (2006) also demonstrated that a single dose of 74 MBq 131 I-L19-SIP caused a maximum reduction in FaDu tumour size at day 18.…”

“…In contrast to RIT using antibodies against tumour cellassociated antigens which are expressed only in certain cancers, such as carcinoembryonic antigen in colorectal tumours (Pedley et al, 2001;Mayer et al, 2003), RIT with L19-SIP antibody, which selectively targets tumour vessels, has the advantage of being effective in a wide range of solid tumours (Berndorff et al, 2005;Spaeth et al, 2006;Tijink et al, 2006). Several options can now be explored to optimise the efficacy of RIT with 131 I-L19-SIP, for example, repeated injection of the antibody.…”

“…Furthermore, several radiolabelled derivatives of the L19 antibody have been studied in biodistribution experiments as well as being evaluated in clinical radioimmunscintigraphy studies (Santimaria et al, 2003). Biodistribution experiments and RIT studies with the L19-SIP antibody have been carried out in tumour-bearing mice and rats, and have demonstrated selective localisation in different tumour models, for example, human melanomas, mouse embryonal teratocarcinomas, human head and neck squamous cell carcinomas, and rat gliomas Berndorff et al, 2005;Spaeth et al, 2006;Tijink et al, 2006). Finally, the therapeutic potential of 131 I-L19-SIP is currently being investigated in clinical trials in Italy and Switzerland (Kaspar et al, 2006).…”

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

“…Comparative analysis of the L19 antibody in scFv, full immunoglobulin G (IgG), and small immunoprotein (SIP) format identified L19SIP as the preferred format for RIT (27,(31)(32)(33). The molecular weight of L19-SIP in its nonreduced form is approximately 80 kDa.…”