Review
Pharmacokinetics and biodistribution of genetically engineered antibodies

https://doi.org/10.1016/S0958-1669(02)00352-XGet rights and content

Abstract

The engineering of monoclonal antibodies has created a new generation of pharmaceuticals with the desired pharmacokinetics and biodistribution properties. For radioimmunotherapy and radioscintigraphy, optimum tumor targeting can be achieved using engineered constructs that provide high antigen affinity and specificity, effective tumor penetration, circulation properties that allow high tumor uptake with acceptable doses to the normal tissues, and fast clearance allowing low background. Recent advances have made possible the development of antibodies with these properties.

Introduction

Monoclonal antibodies (mAbs) are providing an insight into the biology of several malignancies. Some tumor antigens, identified by mAbs, are being used as reliable markers of disease activity. mAbs against tumor-associated antigens (TAAs) are also being used for therapy, either alone as immunologic mediators of cytotoxicity, by blocking receptors or conjugated to a drug, toxin or radionuclide. The efficacy of these conjugated antibodies is limited by their ability to reach their target tumor in adequate quantities without delivering a toxic dose to other tissues. In addition, most of the mAbs are murine in nature and systemic administration of these intact antibodies can lead to the development of a human anti-mouse immunoglobulin antibody (HAMA) response. The HAMA response is usually directed against the constant regions of the immunoglobulin (Ig), but anti-idiotypic responses have also been detected. The HAMA response can reduce the efficacy of subsequent treatment by removing the circulating IgG molecules or antibody fragments, and possibly by altering the pharmacokinetic properties of Fvs.

In the past decade, a new wave of humanized antibodies and antibody fragments has emerged called ‘genetically engineered antibodies’ 1., 2•.. Molecular cloning and the expression of the variable region genes of Ig have greatly facilitated the generation of engineered antibodies. Efforts to minimize the size of proteins capable of recognizing antigens with high-affinity binding have led to the development of Fv fragments of Ig. Their smaller size (25 kDa) makes them potentially more useful than a whole antibody for clinical applications. A single-chain variable antibody fragment (scFv) recombinant protein for a given mAb can be prepared by connecting the genes encoding the heavy chain and light chain variable regions at the DNA level with an appropriate oligonucleotide. The resulting translation product forms a single polypeptide chain with a linker bridging the two variable domains.

This review describes how innovative technology has enabled researchers to engineer intact and small-fragment antibodies with the desired pharmacokinetics and biodistribution properties. Engineered antibodies currently represent over 30% of biological proteins under various clinical trials for cancer diagnosis and therapy [3••].

Section snippets

Engineering of intact antibodies

Several novel strategies have been employed to generate antibody constructs (Fig. 1) with altered pharmacology. Igs have long blood clearance half-lives (T1/2) of up to 3 weeks for major IgG subclasses in human and 5 days in mice. Slow blood clearance greatly reduces the objective of obtaining a high tumor/normal tissue localization ratio as it increases the background in normal tissue (resulting in toxicity) due to its presence in the blood. If clearance is too fast, however, mAbs will not

Small size antibody fragments

When scFv molecules are compared with intact mAbs or more conventional enzymatically derived F(ab′)2 and Fab′ fragments, they offer several advantages as carriers for the selective delivery of radionuclides to tumors. First, the rate of clearance of scFv from the blood pool and normal tissues has been shown to be much more rapid than that seen with intact IgG, F(ab′)2 or Fab′ fragments. This offers the possibility of earlier imaging times and a reduction of the radiation dose to normal tissues

Conclusions

Based on the desired pharmacokinetics, biodistribution and immunogenicity, it seems that genetically engineered antibodies provide new promises for targeted therapy and diagnosis. Multivalent scFvs exhibit a gain in avidity over monovalent scFvs with an improved biological half-life. For RIT applications, these engineered constructs are presenting a therapeutic advantage over parent antibodies. By contrast, due to faster clearance, the monovalent scFvs may be important for clinical imaging

Acknowledgements

Authors on this review article are being supported by grants from the United States Department of Energy (DE-FG02-95ER62024) and the National Institutes of Health (RO1 CA78590 and P50 CA72712). Ellen Graham, administrative assistant, Eppley Institute, University of Nebraska Medical Center, is greatly acknowledged for her editorial assistance.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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