In contrast to the overwhelming success of radiolabeled
antibodies in treating
hematologic malignancies, only modest success has been achieved in the
radioimmunotherapy of solid
tumors. One of the major limitations in successful application of
radioimmunotherapy is the large molecular size of the intact
immunoglobulin that results in prolonged serum half-life and poor
tumor penetration and uptake. With the advent of antibody engineering, small molecular weight
antibody fragments exhibiting improved pharmacokinetics and
tumor penetration have been generated. However, their clinical application has been limited by suboptimal
tumor uptake and short
tumor residence time. There is a greater realization that optimization of the molecular size of the
antibodies alone is not sufficient for clinical success of
radioimmunotherapy. In addition to their size, radiolabeled
antibodies encounter other impediments before reaching their target
antigens expressed on the cell surface of solid
tumors. Some of the barriers include poor blood flow in large
tumors, permeability of vascular endothelium, elevated interstitial fluid pressure of
tumor stroma, and heterogeneous
antigen expression. Recent research has considerably improved our understanding and appreciation of these forces, and the new wave of optimization strategies involves the use of
biological modifiers to modulate the impediments posed by solid
tumors. In combination with radiolabeled
antibodies, various agents are being used to improve the
tumor blood flow, enhance vascular permeability, lower
tumor interstitial fluid pressure by modulating stromal cells and extracellular matrix components, up-regulate the expression of target
antigens, and improve the penetration and retention of the
radiopharmaceuticals. This review outlines ongoing research efforts involving
biological modifiers to optimize the uptake and efficacy of radiolabeled
antibodies for the treatment of solid
tumors.