What are Biopharmaceuticals? Initially: (early 1980) class of therapeutic products produced by modern biotechnology techniques (recombinant DNA technology) or by hybridoma . Mid 2000: monoclonal antibodies not for therapeutic purposes, nucleic acid based therapeutics.   “A biopharmaceutical is a protein or nucleic acid based pharmaceutical substance used for therapeutic or in vivo diagnostic purposes, which is produced by means other than direct extraction from a native (non engineered) biological source’’ Synonyms: biotechnology products, biotechnology medicines, products of pharmaceutical biotechnology The definition includes: recombinant proteins, recombinant antibodies, gene therapy products, antisense oligonucleotides Recombinant technology started in the seventies, today, there are 100 products approved around the world.

The first biopharmaceutical to gain marketing approval was that of ‘humulin’ (recombinant human insulin developed and marketed by Genentech and Eli Lilly), initially approved in the United States in 1982 Approximately 250 million patients had been administered these products and currently in the region of 1 in 4 new molecular entities approved for medical use are biopharmaceuticals The majority of initially approved biopharmaceuticals may be classified as ‘simple replacement proteins’, proteins displaying an identical amino acid sequence to a native human protein and administered in order to replace or augment levels of that protein (FIRST GENERATION BIOPHARMACEUTICALS) Protein Engineering: controlled alteration of the nucleotide sequence of a gene/cDNA coding for a polypeptide, such that specific pre-determined changes in amino acid sequence are introduced with one or more of the following objectives generation of faster/slower acting product; alteration of a protein’s biological half-life alteration of product immunogenicity; (d) generation of novel fused (hybrid) therapeutic proteins SECOND GENERATION BIOPHARMACEUTICALS

Post translational modifications engineering This entails covalent attachment of a chemical group to the polypeptide’s backbone, or the alteration of a pre-existing post-translational modification, such as a glycosylation Pattern Most common is PEGylation: straightforward and generally increases the plasma half-life of the protein drug by reducing the rate of systemic clearance Engineered monoclonal antibodies

Stem cell based therapy Future trends Alternative production systems: Escherichia coli, engineered animal cell lines: CHO, BHK, Saccharomoycese cerevisae Alternative delivery Nucleic acid based therapeutics: gene therapy: many disappointments due to toxic/poor delivery, cancer gene therapy antisesne oligonucleotides: single stranded nucleic acid-based sequences are designed to hybridize with mRNAs, thereby preventing translation siRNA: post translational inhibition of gene expression Stem cell based therapy