ABSTRACT:During the development of any PEGylated protein or peptide, toxicology in relevant species will be conducted prior to human exposure. Normally, comprehensive metabolism data accompany the toxicity studies for a small molecule. We have examined whether such studies would be relevant in the safety assessment of PEGylated material. Literature data indicate that the polyethylene glycol (PEG) associated with a biological molecule should provide no extra concern because the exposure-toxicity relationship of PEG in animals and humans has been thoroughly investigated and metabolism/excretion of PEG is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposure of PEG associated with toxicity in humans, the therapeutic index is large (approximately 600-fold or greater). Therefore, assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.The conjugation of small proteins, peptides, and oligonucleotides with polyethylene glycol (PEG), or PEGylation, has become an increasingly common method of improving the half-life of biological products, mainly through reducing the urinary excretion of the molecule (Yang et al., 2004), but also by reducing the enzymic degradation due to the increased steric bulk (Veronese and Pasut, 2005). In addition, PEGylated biological products often exhibit a reduced affinity for the target receptor compared with the native precursor. This reduced affinity can lead to a lower clearance by target-mediated clearance mechanisms. Finally, the addition of the PEG moiety can have beneficial effects on the immunological profile of a molecule by reducing the ability of the compound to raise antibodies in humans (Mehvar, 2000).PEG is a polymer made up of identical ethylene glycol subunits. PEGs have a descriptor associated with them that represents the mean molecular weight of the molecule (i.e., PEG200 has a molecular weight of 200) (Smyth et al., 1955). The PEG molecules conjugated to proteins can also have the terminal hydroxyl group capped with a methyl group (Molineux, 2003). The structures of these PEGs are detailed in Fig. 1. Higher molecular weight PEGs can have some degree of branching. The PEGs used to conjugate biologicals are polydispersed in nature (i.e., have a range of molecular weights), and this can to lead to a range of drug molecules with potentially subtly different biological properties. The impact of polydispersity must be considered when dealing with these conjugated biological agents (Veronese and Pasut, 2005).To couple the PEG to the protein, peptide, or oligonucleotide, the PEG (generally monomethoxy PEG) is first activated. Several methods can be used to achieve this activation and coupling, including cyanuric chloride, 1,1Ј-carbonyldiimidazole, phenylchloroformate, or succi...
Several serum proteins have been shown to be important in modulating leukocyte chemotaxis and inflammation. We investigated the possibility that the multifunctional serum protein Gc-globulin (vitamin D-binding protein) may also enhance the neutrophil chemotactic activity of complement-derived peptides. Purified Gc-globulin by itself did not induce chemotaxis of human neutrophils. However, as little as 0.01 nM Gc-globulin greatly enhanced the neutrophil chemotactic activity of C5a and its derivative, C5a des Arg over a wide concentration range. The effect was most pronounced at nonchemotactic doses of C5a (0.01 nM) and C5a des Arg (1 nM). Gcglobulin was unable to augment the neutrophil chemotactic activity of FMLP and leukotriene B4. This enhancing activity was not due to a nonspecific effect of anionic proteins since other purified serum proteins, of similar size and charge as Gc-globulin (a, acid glycoprotein, a2 HS glycoprotein, a2 histidine-rich glycoprotein), could not increase the chemotactic activity of C5a des Arg. Serum depleted of Gc-globulin by immunoaffinity chromatography totally lacked chemotactic enhancing activity for C5a des Arg. Gc-globulin-depleted serum activated with zymosan also had significantly less chemotactic activity than control-(sham-depleted) activated serum. Finally, radioiodinated C5a or C5a des Arg formed a 1:1 complex with purified Gc-globulin when analyzed by gel filtration chromatography. These results indicate that Gcglobulin is the major chemotactic enhancing factor in serum and may function as an up-regulator of the chemotactic activity of C5-derived peptides.
A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 +/- 2% at 10 microM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 microg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.
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