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PEGylation reagents

Graph showing the relationship of dPEG® linker length in relation to potency and specificity in extracellular drug conjugates.

Extracellular Drug Conjugates Therapeutically Exploit Protein Proximity

Pharmaceutical company Centrose, founded by James R. Prudent, Ph.D., developed a new class of antibody drug conjugates called extracellular drug conjugates. Nature Publishing Group published the research as a open access paper in its Molecular Therapy journal.1 Apart from the interesting and important development of a new class of antibody drug conjugate (ADC), the research also showed how important linker length 2 is to the potency and specificity of the EDC.

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Amphotericin B+dPEG®: Water-Soluble, Less Toxic, Potent

 

About Amphotericin B

Structure of Amphotericin B. Used with permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.
Figure 1: Structure of Amphotericin B. Image used by permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.

Amphotericin B (Figure 1) is the “gold standard” treatment for systemic fungal infections and diseases caused by the parasite Leishmania. Sometimes it is the only effective treatment because drug resistance renders other treatments useless. Systemic fungal infections are an increasingly serious, widespread problem in medicine. Patients with weakened or suppressed immune systems (caused by HIV/AIDS, diabetes, organ transplants, some cancer treatments) are especially at risk. An estimated 1.5-2 million people die each year from systemic fungal infections (1). Despite its “gold standard” label, Amphotericin B has several well-known difficulties.

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Label monoclonal antibodies site specifically with ETAC reagents

ETAC and labeling monoclonal antibodies

Monoclonal antibodies and their small fragments (Fabs, scFv, diabodies etc.) are intriguing objects for creation of protein-based medicines. These proteins can be site-specifically modified with ETAC-dPEG® (“ETAC” abbreviates “Equilibrium Transfer Alkylation Cross-link”; “dPEG®” is the registered trade name for “discrete Poly(Ethylene Glycol)”) reagents. Using ETAC, a three-carbon bridge is formed linking the two cysteine sulfur atoms. The dPEG® attached to the ETAC reduces the protein’s immunogenicity and prevents rapid clearance of the protein from the bloodstream. This, in turn, helps to maintain a desired therapeutic concentration between doses, thereby reducing the risk of loss of efficacy. The structure of ETAC-reagent and generation of the dPEG®-monosulfone which undergoes a site-specific conjugation with a Fab are outlined below in Figure 1. For details, see, for example, “Comparative binding of disulfide-bridged PEG-Fabs”, Bioconjugate Chemistry (2012), 23, 2262-2277; and “Disulfide bridge based PEGylation of proteins”, Advances in Drug Delivery Reviews (2008), 60, 3-12.

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Superior Surface Protection of Gold Nanoparticles With Short-Chain PEG

Surface protection of gold nanoparticles is improved by using short-chain, alcohol-terminated dPEG® linkers rather than (2-mercaptopropanoyl)glycine (tiopronin) or mercapto-undecyl-tetraethyleneglycol, according to research findings from the lab of David E. Cliffel, Department of Chemistry, Vanderbilt University. Short-chain dPEG®s increase water solubility, are non-toxic, and show no immune response to anti-PEG antibodies at low concentrations.(1)

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Thiol Reactive Crosslinkers for Bioconjugation

Thiol reactive crosslinkers are one of the most common classes of crosslinkers in bioconjugation (1). The popularity of conjugation to a thiol is due in part to its presence in many proteins, but they are not as prevalent as amines, which are another site for conjugation. This will allow for greater control of the conjugation. Even greater control of the conjugation process is afforded if a thiol reactive compound is combined with an amine reactive compound to create a heterobifunctional crosslinker.

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Organophosphorus Hydrolase Pharmacokinetics and Immunogenicity are Improved by Branched dPEG®

Organophosphorus hydrolase  (OPH,EC 8.1.3.1), also known as Aryldialkylphosphatase, is a remarkably stable homodimeric enzyme that can detoxify organophosphate compounds. Organophosphate compounds are the basis of numerous pesticides (e.g., malathion) and chemical warfare weapons (e.g., sarin, VX). Organophosphates act by blocking the action of the enzyme acetylcholinesterase. Overuse and misuse of organophosphate pesticides are major causes of acute pesticide poisoning and death. See also here.

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