Radioiodinated anti-DNA-histone 1 complex chimeric tumor necrosis therapy (TNT) monoclonal antibody 1

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Because neoplastic solid tumors grow rapidly, the lack of sufficient blood supply (and nutrition) leads to cell death and lysis in the lesion and results in the development and accumulation of necrotic areas in the affected areas. As a consequence of the lysis, the nuclear antigens (e.g., DNA, histone proteins, etc.) of the lysed cells are exposed in the necrotic tissues. Investigators have used the exposed antigens to develop monoclonal antibodies (mAbs) that have been radiolabeled for evaluation in preclinical and clinical studies to detect and treat malignant tumors (1). This treatment protocol is known as tumor necrosis therapy (TNT), and the mAb used for this treatment targets only the intracellular antigens present in the necrotic section of a tumor. Although the intact cell membrane of a viable cell does not allow the passage of mAbs (because of their large size), the lysed membrane of a necrotic cell provides mAbs with free access to bind the intracellular antigens, such as DNA-histone complexes, heterochromatic DNA, and single-strand DNA of the lysed cells (2). More than two decades ago, 125I-labeled F(ab’)2 fragments of a mAb designated TNT-1 were shown to bind the nuclear antigens of necrotic cells in xenograft tumors in nude mice. This observation was confirmed with gamma planar imaging using 131I-labeled TNT-1 F(ab’)2 fragments (3). In a subsequent study with nude mice bearing ME-180 cell tumors (of human cervical carcinoma origin), the intact [131I]-TNT-1 mAb was shown to have potential utility in the imaging and therapeutic treatment of the lesions, and it was concluded that treatment success was dependent on the number of necrotic cells present in the tumor (i.e., the higher the number of necrotic cells, the better the treatment results) (4). In another study, the TNT-1 mAb was determined to specifically target the histone H1 protein in nuclear extracts of Raji cells (5). Khawli et al. showed that uptake of the 125I-biotinylated chimeric TNT-1 mAb ([125I]-chTNT-1/B) by LS174T (human colon carcinoma cell line) and Madison 109 (murine adenocarcinoma cell line) cell tumors in mice was superior to that of the parent (non-biotinylated) [125I]-chTNT-1 mAb (2). Biotinylation was reported to improve uptake of the mAb by the tumor because it modified the surface charge, and reduced the circulation time of the molecule. In addition, conjugation of biotin to the mAb decreased the isoelectric point of the molecule and improved its pharmacokinetic properties (2). A 111In-labeled chimeric TNT-3 mAb (targets single-strand DNA), as well as its 111In-labeled Fab’ and F(ab’)2 fragments, were shown to be suitable for the detection of necrotic solid cancerous tumors in mice (6).The mechanism of action of the radioiodinated TNT mAb is believed to be as follows: the mAb binds to the intracellular antigens present in the necrotic sections of a tumor, and the radioactive iodine bound to the mAb generates enough energy (as 90% β radiation (192 keV) and 10% γ radiation (364.5, keV)) to kill the surrounding tumor cells with little damage to the normal tissue (1). [131I]-chTNT-1/B mAb has also been evaluated in a phase I clinical trial for the treatment of advanced colon and colorectal cancers (7) and is under clinical evaluation for the treatment of high-grade adult gliomas (1). In 2003, the Chinese State Food and Drug Administration (CSFDA) approved the use of [131I]-chTNT-1/B mAb for the immunotherapy of advanced lung cancer in China (8).