Can α-Radioimmunotherapy Increase Efficacy for the Systemic Control of Cancer?

Abstract

Benign or partial blocking mAbs that are cancer cell specific can still be effective if labeled with a toxin. The mAb then becomes a targeting vector to transport the toxin to the targeted cancer cells. In such cases, the half-life of the mAb in the body should preferably match the half-life of the toxin. Toxins can be chemicals or radioisotopes and are mostly chelated to the mAb to form relatively stable immunoconjugates. Chemical toxins can have long half-lifes in the body (e.g., ricin), which increases their toxicity for normal tissue. Radioisotopes have both a wide range of half-lifes and radiation decay properties. Nuclear imaging uses long lived g-emitters, allowing blood clearance as the tumor increases its uptake of the conjugate over time, thus improving contrast. I and I, Tl, Ga and In are some reactorand cyclotron-produced radioisotopes for this purpose. b-emitting radioisotopes, predominantly I, are used for therapy. The radioisotopes are generally conjugated with a bifunctional chelator attached to the targeting antibody to form the radio-immunoconjugate (IC). However, the early success of b-emitting radioimmunotherapy has been modest [2]. In recent times, high linear energy transfer (LET) radiation in the form of auger electrons and a-particles have been studied. Auger and Koster-Kronig electron transitions cause the emission of multiple, low-energy and very short-range electrons, such that the LET can still be high. However, the short range requires access into the nucleus to cause single-strand breaks (SSBs) and double-strand breaks (DSBs) in the DNA. a-particles have ranges from 20 to 80 μm and the radioisotope sources can be located on cell membranes or nearby cells. The LET is, typically, approximately 100 keV/μm with a high probability of causing DSBs (although the ratio SSB/DSB is ~20, compared with ~60 for low LET radiation) [3]. a-radiation is ideal for killing Since the development of the hybridoma [1], monoclonal antibodies (mAbs) have been raised against many antigens overexpressed by cancer and other cells [2]. Most of these mAbs are benign with little antibody-dependent cell-mediated cytotoxicity (ADCC), caused by lysis of antibody-coated target cells by effector cells with cytolytic activity and Fc receptors. Cell-mediated cyto toxicity arises from cytolysis of a target cell by effector lymphocytes, such as cytotoxic T lymphocytes or NK cells and may be antibody-dependent or -independent. Another limitation relates to the expression of the targeted antigens being only on a subset of cancer cells. However, some antibodies work by neutralizing or blocking receptors, and these tend to be the more effective. The following antigens and mAbs have been approved by the US FDA for clinical use: