Therapeutic Selection

It has been roughly fifty years since the humoral immune response was first conceived of as a compelling example of evolution via selection of individual cells on a time scale that is short relative to standard organismal evolution (Talmage, 1957, Burnet, 1957; reviewed by Forsdyke, 1995).  Multiple lines of evidence supportive of this concept were forthcoming over the next fifteen years (briefly reviewed in Talmage, 1986).   Instead of individual organisms competing for multiple resources that facilitate reproduction through mating, B lymphocytes compete, through cell surface versions of the immunoglobulin molecules they will ultimately secrete, for binding to antigen molecules that with other inputs stimulate cellular proliferation.  The descendants of the B cells expressing the receptors best able to complex noncovalently with the antigens introduced into the body will tend to dominate the B lymphocyte population at subsequent times.  Thus, the B cell population evolves in a neo-Darwinian fashion, i.e. the clonal composition of the population changes over time.

Numerous methods have been developed to exploit similar processes in vitro for the purposes of research.  A previous post (http://evomed.org/?p=145) provided one example of such in vitro selection which was used for the purpose of producing an antibody able to bind to the hemaggluitinin molecules of multiple type A influenza virus subtypes.  An article that appeared in March of this year by Bostrom et al.(2009), at Genentech, describes a novel application of selection techniques to producing a an antibody capable of potential use as a therapeutic agent in cancer.  Elsewhere (Greenspan, 2009), I have explained why some of the claims made for the broader significance of this paper were over-stated, but my dissatisfaction with the paper on that score does not diminish my appreciation for the originality of the question addressed or for the impressive manner in which an array of sophisticated methods were deployed.

Herceptin® (trastuzumab) is an antibody with specificity for the human epidermal growth factor receptor 2 (HER2) that is used to treat patients whose tumor cells overexpress HER2.  Earlier studies (Kelley and O’Connell, 1993; Cho et al., 2003) characterized the interaction between Herceptin® and HER2 and suggested that it binds to this antigen primarily through energetic contributions from amino acids in the heavy chain variable domain, with lesser contributions from the amino acids in the light chain variable domain.  This asymmetry led the authors to wonder if they could mutagenize solvent accessible amino acid residues the light chain variable domain and select for recognition of a second antigen, vascular endothelial growth factor (VEGF), which is also a therapeutic target in breast carcinoma and other cancers, while retaining the reactivity with the original ligand, HER2.

The authors were successful in selecting Herceptin variants that bound both HER2 and VEGF with affinities in the 10-200 nM range or better.  Studies in mouse tumor models suggested that a Herceptin-derived antibody, called bH1-44, was approximately as effective in limiting tumor growth using either breast or colon carcinoma cell lines in vivo as, respectively, Herceptin or bevacizumab (a VEGF-specific antibody used clinically under the brand name Avastin®).

It remains to be determined in patients whether antibodies like bH1-44, with dual specificities are actually better than Herceptin or bevacizumab alone or than a combination of the two antibodies.  Regardless of the ultimate clinical utility of this particular exercise, it demonstrates the potential for mutation and selection strategies to generate therapeutic agents with unique functional attributes.

References

Talmage DW. Allergy and immunology. Annu Rev Med. 1957;8:239-56.

Burnet, F. 1957. A modification of Jerne’s theory of antibody production using the concept of clonal selection. Aust. J. Sci. 20: 67-68.

Talmage DW. The acceptance and rejection of immunological concepts. Annu Rev Immunol. 1986;4:1-

Forsdyke DR. The origins of the clonal selection theory of immunity as a case study for evaluation in science. FASEB J. 1995 Feb;9(2):164-6.

Greenspan N. May 14, 2009. Application of selection to a clinically-important infectious disease. http://evomed.org/?p=145.

Bostrom J, Yu SF, Kan D, Appleton BA, Lee CV, Billeci K, Man W, Peale F, Ross S, Wiesmann C, Fuh G. Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science. 2009 Mar 20;323(5921):1610-4.

Greenspan, N. April 15, 2009. The hype of science. http://www.the-scientist.com/news/display/55617/.

Kelley RF, O’Connell MP. Thermodynamic analysis of an antibody functional epitope. Biochemistry. 1993 Jul 13;32(27):6828-35.

Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, Leahy DJ. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature. 2003 Feb 13;421(6924):756-60.