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A Look Ahead: Bioconjugates BioPharmThe Science & Business of Biopharmaceuticals Electronically reprinted from January 2013 Bioconjugates: The Adaptable Challenge

Trishul Shah ith the advent of whole- PEGs, however, has also been used suc- genome sequence cessfully for extending the half-life of W projects, a wealth of proteins and by preventing information has been enzymatic degradation and renal clear- attained and continues to be acquired ance (1, 2). The half-life of bioconju- Conjugation about biomolecules and their biological gates is dependent on the in vivo rate of processes. The information has led to the degradation of the conjugate (i.e., PEG, of a biologic discovery of numerous new and HES, XTEN, or HSA), and therefore, for protein therapeutics based on these enti- any given dosage, the half-life of the to a carrier ties; however, there a number of chal- bioconjugate cannot be longer than the lenges facing potential therapeutics that half-life of the itself. molecule can include delivery, compliance, and half- life. The burgeoning field of bioconju- PEGYLATED PRODUCTS solve problems gation provides a route to overcoming ADAGEN (PEG-bovine adenos- in solubility some of these challenges. ine deaminase) manufactured by Bioconjugation is the covalent Enzon Pharmaceuticals was the first and stability, derivatization of biomolecules such PEGylated protein approved by FDA in as protein, peptides, oligonucleotides, March 1990. It is used to treat X-linked but introduces and antibodies. Bioconjugates are gain- severe combined immunogenicity ing popularity because of their ver- syndrome, as an alternative to bone its own set of satility in a number of applications. marrow transplantation and enzyme Bioconjugates, such as fluorescent replacement by gene therapy. Since challenges. molecules and biotin, can be used as the introduction of ADAGEN, a large probes and diagnostic aids for imag- number of PEGylated protein and pep- ing. Larger conjugates, such as poly- tide pharmaceuticals have followed, ethyleneglycol (PEG), are being used and many others are under clinical in therapeutic areas to enhance water trial or under development stages (see solubility, reduce immunogenicity, and Tables I and II). On Mar. 27, 2012, FDA increase in vivo circulation half-life. announced the approval of the first Most peptides composed of naturally PEGylated peptide, Peginesatide, for the occurring L-amino acids have short treatment of anemia associated with half-lives, often measured in minutes chronic kidney disease. in vivo. Considerable effort has been Although PEG has been successfully invested in stabilizing peptidic drug used in increasing the half-life of pro- substances either by chemical modifi- teins and peptides, there are some chal- cation or by incorporating the peptide lenges and concerns, in particular, risk into a matrix that slowly releases the associated with chronic administration pharmaceutical active into its environ- of high dose PEGylated peptides (3). ment. Chemical modification by intro- Although, PEGs can be filtered through Trishul Shah is the business duction of D- and exotic amino acids, the kidneys over time, high doses of development key account manager as well as C- and N-terminal capping, PEGylated peptides and proteins can for the PolyPeptide Group, are still viable techniques for protecting cause accumulation of the bioconju- North America, Torrance, CA. peptides from enzymatic degradation. gate at the target organ and at other [email protected]. The use of conjugation agents such as organs in the body. The clearance rate A Look Ahead: Bioconjugates

Table I: Table of PEGylated pharmaceuticals (brand name) currently on the market in reverse chronology by FDA approval year with sponor and indication.

Drug Sponsor FDA Approval Indication

Omontys Affymax/Takeda 2012 Anaemia associated with chronic kidney dise