PUBLICATIONS

Importance of the field: The number of disease-associated protein targets has significantly increased over the past decade due to advances in molecular and cellular biology technologies, human genetic mapping efforts and information gathered from the human genome project. The identification of gene products that appear to be involved in supporting the underlying cause of disease has offered the biopharmaceutical industry an opportunity to develop compounds that can specifically target these molecules. This targeted therapy may, in turn, improve therapeutic responses and lower the risk of unwanted side effects that are commonly seen in traditional small chemical-based medicines.

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Over the past decade, therapeutic proteins and monoclonal antibodies (mAbs) have become one of the most successful classes of pharmaceutical agents because they can replace or block specific targets associated with disease.

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The reversible inhibition of DNA repair is a novel approach to maximize genetic diversity within a plant’s genome in order to generate offspring exhibiting important de novo output traits. This process is based on the inhibition of the evolutionarily conserved mismatch repair (MMR) system. In this process, a human dominant negative MMR gene allele is introduced into the germline of a target plant, yielding progeny that can be screened to identify variants with commercially important agronomic output traits. Using this novel strategy, we generated MMR-deficient Arabidopsis thaliana plants that showed genome-wide instability of nucleotide repeats associated with chromosomal microsatellites, in addition to base substitution mutations.

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ABSTRACT: Mutations in DNA mismatch repair (MMR) genes lead to genetically hypermutable cells. Germline mutations in MMR genes in man have been linked to the genetic predisposition to hereditary nonpolyposis colon cancer and a number of other inherited and sporadic malignancies. The ability to modulate the MMR process (referred to as morphogenics) in model systems offers a powerful tool for generating functional diversity in cells and multicellular organisms via the perpetual genomewide accumulation of randomized point and slippage mutation(s).

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Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ line mutations in MMR genes predispose kindreds to HNPCC suggest a “two-hit” inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells containing a wild-type hPMS2 allele. These results have significant implications for understanding the relationship between mutagenesis and carcinogenesis and the ability to generate mammalian cells with mutator phenotypes.

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The concept of using antibodies as therapeutics to cure human diseases was postulated nearly 100 years ago by Paul Ehrlich and subsequently enabled by the discovery of hybridoma technology by Kohler and Milstein in 1975. While the use of monoclonal antibodies (mAbs) as drugs that can specifically target a disease-associated antigen is compelling, it has taken a quarter century for these molecules to be adopted as bona fide therapeutic agents. Despite their slow pursuit in drug development during the pioneering years, it is now estimated that there are nearly 500 mAb-based therapies in development. Major factors that have influenced the acceptance of monoclonal antibodies as therapeutics include their drug safety profiles, technological advancements for facilitating mAb discovery and development, and market success.

The Monoclonal antibodies (MAbs) represent the fastest growing segment of the biopharmaceutical market, with sales that totaled greater than US $3 billion in 2002 and have been projected to grow up to over $5 billion by 2005. A survey by the Pharmaceutical Research and Manufacturers of America of 144 companies lists 75 MAbs among the 371 biotechnology-based medicines currently in clinical development (1). The dramatic success of antibodies as therapeutics has created substantial value for companies developing such products (2, 3).

ABSTRACT: Folate receptor alpha (FRA) is a cell surface protein whose aberrant expression in malignant cells has resulted in its pursuit as a therapeutic target and marker for diagnosis of cancer.  The development of immune-based reagents that can reproducibly detect FRA from patient tissue processed by varying methods has been difficult due to the complex post-translational structure of the protein whereby most reagents developed to date are highly structure-sensitive and have resulted in equivocal expression results across independent studies.  The aim of the present study was to generate novel monoclonal antibodies (mAbs) using modified full length FRA protein as ummunogen in order to develop a panel of mAbs to various, non-overlapping epitopes that may serve as diagnostic reagents able to robustly detect FRA-specific mAbs that are able to specifically detect FRA using an array of diagnostic platforms and methods.  In addition, the methods used to develop these mAbs and their diverse binding properties provide additional information on the three dimensional structure of FRA in its native cell surface configuration.

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