Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-cd9895bd7-fscjk Total loading time: 0 Render date: 2024-12-22T23:26:11.683Z Has data issue: false hasContentIssue false

19 - Polymer Fusions to Increase Antibody Half-Lives: PEGylation and Other Modifications

from PART VIII - PROLONGATION OF SERUM HALF-LIFE

Published online by Cambridge University Press:  15 December 2009

By
Sam P. Heywood  and
David P. Humphreys
Edited by
Melvyn Little
Melvyn Little
Affiliation:
Affimed Therapeutics AG
Get access

Summary

PEGylation of proteins has been performed for over 30 years (Abuchowski et al., 1977a,b). Although the details such as polyethylene glycol (PEG) size, structure, synthesis, purification, and reactive chemistries have changed, the basic aims of the method remain the same. These aims are to improve the biophysical and pharmaceutical characteristics of proteins by modifying pharmacokinetics (circulating serum half-life); increasing resistance to proteolysis; reducing antigenicity and immunogenicity; and in some instances, increasing solubility and reducing propensity to aggregate. These improvements have been demonstrated successfully in the clinic with a variety of proteins including enzymes, cytokines, and antibodies. In this chapter we will introduce the aspects of PEGylation common to all proteins before dealing with their specific application to antibodies and antibody fragments.

POLYMERS FOR PROTEIN CONJUGATION

Many potential therapeutic proteins have characteristics that can be improved by conjugation to large water-soluble polymers. Tailoring of these characteristics is required in order to generate the most effective therapeutic. Alteration of a protein's characteristics may also expand its use, for example, from single use in acute indications to repeat dosing in chronic indications. Conjugation of both small molecule and protein-based drugs to a diverse range of polymers has been investigated in order to improve their therapeutic profile.

Type
Chapter
Information
Recombinant Antibodies for Immunotherapy , pp. 275 - 292
Publisher: Cambridge University Press
Print publication year: 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abuchowski, A., Es, T., Palczuk, N.C., and Davis, F.F.. 1977a. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J. Biol. Chem. 252:3578–3581.Google ScholarPubMed
Abuchowski, A., McCoy, J.R., Palczuk, N.C., Es, T., and Davis, F.F.. 1977b. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J. Biol. Chem. 252:3582–3586.Google ScholarPubMed
Albrecht, H., Burke, P.A., Natarajan, A., Xiong, C.Y., Kalicinsky, M., Denardo, G.L., and Denardo, S.J.. 2004. Production of soluble scFvs with C-terminal-free thiol for site-specific conjugation or stable dimeric scFvs on demand. Bioconj. Chem. 15:16–26.CrossRefGoogle ScholarPubMed
Albrecht, H., Denardo, G.L., and Denardo, S.J.. 2006. Monospecific bivalent scFv-SH: effects of linker length and location of an engineered cysteine on production, antigen binding activity and free SH accessibility. J. Immunol. Meth. 310:100–116.CrossRefGoogle ScholarPubMed
Bailon, P., Palleroni, A., Schaffer, C.A., Spence, C.L., Fung, W.J., Porter, J.E., Ehrlich, G.K., Pan, W., Xu, Z.X., Modi, M.W., Farid, A., and Berthold, W.. 2001. Rational design of a potent, long-lasting form of interferon: A 40kDa branched polyethylene glycol-conjugated interferon α-2a for the treatment of hepatitis C. Bioconj. Chem. 12:195–202.CrossRefGoogle Scholar
Balan, S., Choi, J.W., Godwin, A., Teo, I., Laborde, C.M., Heidelberger, S., Zloh, M., Shaunak, S., and Brocchini, S.. 2007. Site-specific PEGylation of protein disulfide bonds using a three carbon bridge. Bioconj. Chem. 18:61–76.CrossRefGoogle ScholarPubMed
Basu, A., Et, A.L., and Filpula, D.. 2006. Structure-function engineering of interferon-β-1b for improving stability, solubility, potency, immunogenicity, and pharmacokinetic properties by site-selective mono-PEGylation. Bioconj. Chem. 17:618–630.CrossRefGoogle ScholarPubMed
Baudys, M., Letourneur, D., Liu, F., Mix, D., Jozefonvicz, J., and Kim, S.W.. 1998. Extending insulin action in vivo by conjugation to carboxymethyl dextran. Bioconj. Chem. 9:176–183.CrossRefGoogle ScholarPubMed
Bazin-Redureau, M.I., Renard, C.B., and Scherrmann, J.M.G.. 1997. Pharmacokinetics of heterologous and homologous immunoglobulin G, F(ab′)2 and Fab after intravenous administration in the rat. J. Pharmaceut. Pharmacol. 49:277–281.CrossRefGoogle ScholarPubMed
Begg, G.E., and Speicher, D.W.. 1999. Mass spectrometry detection and reduction of disulfide adducts between reducing agents and recombinant proteins with highly reactive cysteines. J. Biomol. Techniques. 10:17–20.Google ScholarPubMed
Bendele, A., Seely, J., Richey, C., Sennello, G., and Shopp, G.. 1998. Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. Toxicological Sci. 42:152–157.CrossRefGoogle ScholarPubMed
Bray, J., Robinson, B.G., and Byrne, J.. 1984. Influence of charge on filtration across renal basement membranes on films in vitro. Kidney Interntl. 25:527–533.CrossRefGoogle ScholarPubMed
Brocchini, S., Balan, S., Godwin, A., Choi, J.W., Zloh, M., and Shaunak, S.. 2006. PEGylation of native disulphide bonds in proteins. Nature Protocols. 1:2241–2252.CrossRefGoogle ScholarPubMed
Brown, B.A., Corneau, R.D., Jones, P.L., Libertore, F.A., Neacy, W.P., Sands, H., and Gallagher, B.M.. 1987. Pharmacokinetics of the monoclonal antibody B72.3 and its fragments labelled with either 125I or 111In. Cancer Res. 47:1149–1154.Google ScholarPubMed
Buist, M.R., Kenemans, P., Hollander, W., Vermorken, J.B., Molthoff, C.J.M., Burger, C.W., Helmerhorst, T.J.M., Baak, J.P.A., and Roos, J.C.. 1993. Kinetics and tissue distribution of the radiolabeled chimeric monoclonal antibody Mov18 IgG and F(ab′)2 fragments in ovarian carcinoma patients. Cancer Res. 53:5413–5418.Google Scholar
Caliceti, P., Schiavon, O., and Veronese, F.M.. 1999. Biopharmaceutical properties of uricase conjugated to neutral and amphiphilic polymers. Bioconj. Chem. 10:638–646.CrossRefGoogle ScholarPubMed
Chang, R.L.S., Ueki, I.F., Troy, J.L., Deen, W.M., Robertson, C.R., and Brenner, B.M.. 1975. Permselectivity of the glomerular capillary wall to macromolecules. Biophysical J. 15:887–906.CrossRefGoogle ScholarPubMed
Chapman, A.P., Antoniw, P., Spitali, M., West, S., Stephens, S., and King, D.J.. 1999. Therapeutic antibody fragments with prolonged in vivo half-lives. Nature Biotechnol. 17:780–783.CrossRefGoogle ScholarPubMed
Chapman, A.P. 2002. PEGylated antibodies and antibody fragments for improved therapy: a review. Adv. Drug Del. Reviews. 54:531–545.CrossRefGoogle ScholarPubMed
Covell, D.G., Barbet, J., Holton, O.D., Black, C.D.V., Parker, R.J., and Weinstein, J.N.. 1986. Pharmacokinetics of monoclonal Immunoglobulins γ1, F(ab′)2, and Fab′ in Mice. Cancer Res. 46:3969–3978.Google Scholar
Cunningham-Rundles, C., Zhuo, Z.H.O.U., Griffith, B., and Keenan, J.. 1992. Biological activities of polyethylene-glycol immunoglobulin conjugates. J. Immunol. Meth. 152:177–190.CrossRefGoogle ScholarPubMed
Davis, S., Abuchowski, A., Park, Y.K., and Davis, F.F.. 1981. Alteration of the circulating life and antigenic properties of bovine adenosine deaminase in mice by attachment of polyethylene glycol. Clin. Exp. Immunol. 46:649–652.Google ScholarPubMed
Delgado, C., Pedley, R.B., Herraez, A., Boden, R., Boden, J.A., Keep, P.A., Chester, K.A., Fisher, D., Begent, R.H.J., and Francis, G.E.. 1996. Enhanced tumour specificity of an anti-carcinoembrionic antigen Fab fragments by poly(ethylene glycol) (PEG) modification. Brit. J. Cancer. 73:175–182.CrossRefGoogle ScholarPubMed
Duncan, R. 2003. The dawning era of polymer therapeutics. Nature Rev. 2:347–360.Google ScholarPubMed
Fagnani, R., Hagan, M.S, and Bartholomew, R. 1990. Reduction of immunogenicity by covalent modification of murine and rabbit immunoglobulins with oxidized dextrans of low molecular weight. Cancer Res. 50:3638–3645.Google ScholarPubMed
Gillies, E.R., Dy, E., Frechet, J.M.J., and Szoka, F.C.. 2005. Biological evaluation of polyester dendrimer: poly(ethylene oxide) “bow-tie” hybrids with tunable molecular weight and architecture. Mol. Pharmaceutics. 2:129–138.CrossRefGoogle ScholarPubMed
Gregoriadis, G., Fernandes, A., Mital, M., and McCormack, B.. 2000. Polysialic acids: potential in improving the stability and pharmacokinetics of proteins and other therapeutics. Cellular Mol. Life Sci. 57:1964–1969.CrossRefGoogle ScholarPubMed
Grene-Lerouge, N.A.M., Bazin-Redureau, M.I., Debray, M., and Scherrmann, J.M.G.. 1996. Interspecies scaling of clearance and volume of distribution for digoxin-specific Fab. Toxicol. Appl. Pharmacol. 138:84–89.CrossRefGoogle ScholarPubMed
Gutiérrez, J.M., Leon, G., and Lomonte, B.. 2003. Pharmacokinetic-pharmacodynamic relationships of immunoglobulin therapy for envenomation. Clin. Pharmacokinetics. 42:721–741.CrossRefGoogle ScholarPubMed
Han, H.D., Lee, A., Hwang, T., Song, C.K., Seong, H., Hyun, J., and Shin, B.C.. 2007. Enhanced circulation time and antitumour activity of doxorubicin by comb-like polymer-incorporated liposome. J. Controlled Rel. 120:161–168.CrossRefGoogle Scholar
Humphreys, D.P., Heywood, S.P., Henry, A., Ait-Lhadj, L., Antoniw, P., Palframan, R., Greenslade, K.J., Carrington, B., Reeks, D.G., Bowering, L.C., West, S., and Brand, H.A.. 2007. Alternative antibody Fab fragment PEGylation strategies: combination of strong reducing agents, disruption of the interchain disulphide bond and disulphide engineering. Prot. Eng. Des. Sel. 20: 227–234.CrossRefGoogle ScholarPubMed
Humphreys, D.P. 2003. Production of antibodies and antibody fragments in Escherichia coli and a comparison of their functions, uses and modification. Cur. Opin. Drug Dis. Devel. 6:188–196.Google Scholar
Hurwitz, E. 1983. Specific and nonspecific macromolecule-drug conjugates for the improvement of cancer chemotherapy. Biopolymers. 22:557–567.CrossRefGoogle ScholarPubMed
Jultani, A., Li, C., Ozen, M., Yadav, M., Yu, S., Wallace, S, and Pathak, S. 1997. Paclitaxel and water-soluble poly(L-glutamic acid)-paclitaxel, induce direct chromosomal abnormalities and cell death in a murine metastatic melanoma cell line. Anticancer Res. 17:4269–4274.Google Scholar
Kamisaki, Y., Wada, H., Yagura, T., Matsushima, A., and Inada, Y.. 1981. Reduction in immunogenicity and clearance rate of Escherichia coli L-asparaginase by modification with monomethoxypolyethylene glycol. J. Pharmacol. Exp. Therapeutics. 216:410–414.Google ScholarPubMed
Kaneda, Y., Tsutsumi, Y., Yoshioka, Y., Kamada, H., Yamamoto, Y., Kodaira, H., Tsunoda, S., Okamoto, T., Mukai, Y., Shibata, H., Nakagawa, S., and Mayumi, T.. 2004. The use of PVP as a polymeric carrier to improve plasma half-life of drugs. Biomaterials. 25:3259–3266.CrossRefGoogle ScholarPubMed
Keyler, D.E., Salerno, D.M., Mukakami, M.M., Ruth, G., and Pentel, P.R.. 1991. Rapid administration of high-dose human antibody Fab fragments to dogs: pharmacokinetics and toxicity. Fund. Appl. Toxicol. 17:83–91.CrossRefGoogle ScholarPubMed
King, D.J., Turner, A., Farnsworth, A.P.H., Adair, J.R., Owens, R.J., Pedley, B., Baldock, D., Proudfoot, K.A., Lawson, A.D.G., Beeley, N.R.A., Millar, K., Millican, T.A., Boyce, B.A., Antoniw, P., Mountain, A., Begent, R.H.J., Shochat, D., and Yarranton, G.T.. 1994. Improved tumour targeting with chemically cross-linked recombinant antibody fragments. Cancer Res. 54:6176–6185.Google ScholarPubMed
Kitamura, K., Takahashi, T., Takashina, K.I., Yamaguchi, T., Noguchi, A., Tsurumi, H., Tokokuni, T., and Hakomori, S.I.. 1990. Polyethylene glycol modification of the monoclonal antibody A7 enhances its tumour localization. Biochem. Biophys. Res. Comms. 171:1387–1394.CrossRefGoogle Scholar
Knight, D.M., Jordan, R.E., Kruszynski, M., Tam, S.H., Gile-Komar, J., Treacy, G., and Heavner, G.A.. 2004. Pharmacodynamic enhancement of the anti-platelet antibody Fab abciximab by site-specific PEGylation. Platelets. 15:409–418.CrossRefGoogle ScholarPubMed
Kobayashi, H., Le, N., Kim, I.S., Kim, M.K., Pie, J.E., Drumm, D., Paik, D.S., Waldmann, T.A., Paik, C.H., and Carrasquillo, J.A.. 1999. The pharmacokinetic characteristics of glycolated humanized anti-Tac Fabs are determined by their isoelectric points. Cancer Res. 59:422–430.Google ScholarPubMed
Koumenis, I., Shahrokh, Z., Leong, S., Hsei, V., Deforge, L., and Zapata, G.. 2000. Modulating pharmacokinetics of an anti-interleukin-8 F(ab′)2 by amine-specific PEGylation with preserved bioactivity. Interntl. J. Pharmaceutics. 198:83–95.CrossRefGoogle ScholarPubMed
Krinner, E.M., Hepp, J., Hoffmann, P., Bruckmaier, S., Petersen, L., Petsch, S., Parr, L., Schuster, I., Mangold, S., Lorenczewski, G., Strasser, M., Itin, C., Wolf, A., Basu, A., Yang, K., Filpula, D., Sorensen, P., Kufer, P., Baeuerle, P., and Raum, T.. 2006. A highly stable polyethylene glycol-conjugated human single-chain antibody neutralizing granulocyte-macrophage colony stimulating factor at low nanomolar concentration. Prot. Eng. Des. Sel. 19:461–470.CrossRefGoogle ScholarPubMed
Kubetzko, S., Sarkar, C.A., and Plückthun, A.. 2005. Protein PEGylation decreases observed target association rates via a dual blocking mechanism. Mol. Pharmacol. 68:1439–1454.CrossRefGoogle Scholar
Kubetzko, S., Balic, E., Waibel, R., Zangemeister-Wittke, U., and Plückthun, A.. 2006. PEGylation and multimerization of the anti-p185HER-2 single chain Fv fragment 4D5. J. Biol. Chem. 46:35186–35201.CrossRefGoogle Scholar
Leong, S.R., Deforge, L., Presta, L., Gonzalez, T., Fan, A., Reichert, M., Chuntharapai, A., Kim, K.J., Tumas, D.B., Lee, W.P., Gribling, P., Snedecor, B., Chen, H., Hsei, V., Schoenhoff, M., Hale, V., Deveney, J., Koumenis, I., , E. and Zapata, G.. 2001. Adapting pharmacokinetic properties of a humanised anti-interleukin-8 antibody for therapeutic applications using site-specific PEGylation. Cytokine. 16:106–119.CrossRefGoogle Scholar
Li, L., Yazaki, P.J., Anderson, A.L., Crow, D., Colcher, D., Wu, A.M., Williams, L.E., Wong, J.Y.C., Raubitschek, A., and Shively, J.E.. 2006. Improved biodistribution and radioimmunoimaging with poly(ethylene glycol)-DOTA-conjugated anti-CEA diabody. Bioconj. Chem. 17:68–76.CrossRefGoogle ScholarPubMed
Loiseau, F.A., Hii, K.K., and Hill, A.M.. 2004. Multigram synthesis of well defined extended bifunctional polyethylene glycol (PEG) chains. J. Organic Chem. 69:639–647.CrossRefGoogle ScholarPubMed
Maack, T., Johnson, V., Kau, S.T., Figueredo, J., and Sigulem, D.. 1979. Renal filtration, transport, and metabolism of low-molecular-weight proteins: A review. Kidney Interntl. 16:251–270.CrossRefGoogle ScholarPubMed
Mabry, R., Rani, M., Geiger, R., Hubbard, G.B., Carrion, R., Brasky, K., Patterson, J.L., Georgiou, G., and Iverson, B.L.. 2005. Passive protection against anthrax by using a high affinity antitoxin antibody fragment lacking an Fc region. Infect. Immunity. 73:8362–8368.CrossRefGoogle ScholarPubMed
Macfarlane, D.J., Smart, R.C., Tsui, W.W., Gerometta, M., Eisenberg, P.R., and Scott, A.M.. 2006. Safety, pharmacokinetic and dositmetry evaluation of the proposed thrombus imaging agent 99mTc-DI-DD-3B6/22-80B3 Fab. Eur. J. Nucl. Med. Molec. Imaging. 33:648–656.CrossRefGoogle ScholarPubMed
Matsumura, Y., and Maeda, H.. 1986. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumour agents SMANCS. Cancer Res. 46:6387–6392.Google Scholar
Matsushima, A., Nishimura, H., Ashihara, Y., Yakata, Y., and Inada, Y.. 1980. Modification of E. coli asparaginase with 2,4-bis (o-methoxypolyethylene glycol)-6-chloro-s-triazine (activated PEG2); disappearance of binding towards anti-serum and retention of enzymatic activity. Chem. Letts.: 773–776.CrossRefGoogle Scholar
McDonagh, C.F., Turcot, E., Westendorf, L., Webster, J.B., Alley, S.C., Kim, K., Andreyka, J., Stone, I., Hamblett, K.J., Francisco, J.A., and Carter, P.. 2006. Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment. Prot. Eng. Des. Sel. 19:299–307.CrossRefGoogle ScholarPubMed
Milenic, D.E., Yokota, T., Filpula, D.R., Finkelman, M.A.J., Dodd, S.W., Wood, J.F., Whitlow, M., Snoy, P., and Schlom, J.. 1991. Construction, binding properties, metabolism, and tumour targeting of a single chain Fv derived from the pancarcinoma monoclonal antibody CC49. Cancer Res. 51:6363–6371.Google ScholarPubMed
Monfardini, C., Schiavon, O., Caliceti, P., Morpurgo, M., Harris, J.M., and Veronese, F.M.. 1995. A branched monomethoxypoly (ethylene glycol) for protein modification. Bioconj. Chem. 6:62–69.CrossRefGoogle ScholarPubMed
Mozier, N.M. 2003. Antibody PEG positional isomers, compositions comprising same and use thereof. WO 03/099226 A2.
Natarajan, A., Xiong, C.Y., Albrecht, H., Denardo, G.L., and Denardo, S.J.. 2005. Characterization of site-specific scFv PEGylation for tumor-targeting pharmaceuticals. Bioconj. Chem. 16:113–121.CrossRefGoogle ScholarPubMed
Onda, M., Vincent, J.J, Lee, B, and Pastan, I. 2003. Mutants of immunotoxin anti-Tac (dsFv)-PE38 with variable number of lysine residus as candidates for site-specific chemical modification. 1. Properties of mutant molecules. Bioconj. Chem. 14:480–487.CrossRefGoogle Scholar
Pedley, R.B., Boden, J.A., Boden, R., Begent, R.H.J., Turner, A., Haines, A.M.R., and King, D.J.. 1994. The potential for enhanced tumour localisation by poly (ethylene glycol) modification of anti-CEA antibody. Brit. J. Cancer. 70:1126–1130.CrossRefGoogle ScholarPubMed
Rabkin, R., and Dahl, D.C. 1993. Hormones and the kidney. In Diseases of the Kidney (5th ed), edited by Schrier, R.B. and Gottschalk, C.W.Boston: Little, Brown and Company, pp. 283–334.Google Scholar
Richter, A.W., and Åkerblom, E.. 1983. Antibodies against polyethylene glycol produced in animals by immunisation with monomethoxy polyethylene glycol modified proteins. Interntl. Arch. Allergy Appl. Immunol. 70:124–131.CrossRefGoogle ScholarPubMed
Richter, A.W., and Åkerblom, E.. 1984. Polyethylene glycol reactive antibodies in man: titer distribution in allergic patients treated with monomethoxy polythylene glycol modified allergens of placebo, and in healthy blood donors. Interntl. Arch. Allergy Appl. Immunol. 74:36–39.CrossRefGoogle ScholarPubMed
Rolan, P., Baker, M., Stringer, F., and Stephens, S.. 2008. Pharmacokinetics of certolizumab pegol (CDP870), a PEGylated Fab anti-TNFα monoclonal antibody. Brit. J. Clin. Pharmacol. in press.Google Scholar
Rose-John, S., and Schooltink, H.. 2003. CDP-870 Celltech/Pfizer. Curr. Opin. Investl. Drugs. 4:588–592.Google ScholarPubMed
Sato, H. 2002. Enzymatic procedure for site-specific pegylation of proteins. Adv. Drug Del. Rev. 54:487–504.CrossRefGoogle ScholarPubMed
Schlapschy, M., Theobald, I., Mack, H., Schottelius, M., Wester, H.J., and Skerra, A.. 2007. Fusion of a recombinant antibody fragment with a homo-amino-acid polymer: effects on biophysical properties and prolongues plasma half-life. Prot. Eng., Des. Sel. 20:273–284.CrossRefGoogle Scholar
Schreiber, S., Khaliq-Kareemi, M., Lawrance, I.C., Thomsen, O.Ø.Hanauer, S.B., McColm, J., Bloomfield, R., and Sandborn, W.J.. 2007. Maintenance therapy with certolizumab pegol for crohn's disease. New Eng. J. Med. 357:239–250.CrossRefGoogle ScholarPubMed
Shaunak, S., Godwin, A., Choi, J.W., Balan, S., Pedone, E., Vijayarangam, D., Heidelberger, S., Teo, I., Zloh, M., and Brocchini, S.. 2006. Site-specific PEGylation of native disulfide bonds in therapeutic proteins. Nat. Chemical Biol. 2:312–313.CrossRefGoogle ScholarPubMed
Soucek, J., Pouckova, P., Strohalm, J., Plocova, D., Hlouskova, D., Zadinova, M., and Ulbrich, K.. 2002. Poly(N-2(2-hydroxypropyl)methylacrylamide) conjugates of bovine pancreatic ribonuclease (RNase A) inhibit growth of human melanoma in nude mice. J. Drug Targeting. 10:175–183.CrossRefGoogle Scholar
Suzawa, T., Nagamura, S., Saito, H., Ohta, S., Hanai, N., Kanazawa, J., Okabe, M., and Yamasaki, M.. 2002. Enhanced tumor cell selectivity of adriamycin-monoclonal antibody conjugate via a poly(ethylene glycol)-based cleavable linker. J. Controlled Rel. 79:229–242.CrossRefGoogle Scholar
Trakas, N., and Tzartos, S.J.. 2001. Conjugation of acetylcholine receptor-protecting Fab fragments with polyethylene glycol results in a prolonged half-life in the circulation and reduced immunogenicity. J. Neuroimmunol. 120:42–49.CrossRefGoogle Scholar
Tsutsumi, Y., Onda, M., Nagata, S., Lee, B., Kreitman, R.J., and Pastan, I.. 2000. Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) improves antitumour activity and reduces animal toxicity and immunogenicity. Pro. Natl. Acad. Sci., U.S.A. 97:8548–8553.CrossRefGoogle Scholar
Ujhelyi, M.R., and Robert, S.. 1995. Pharmacokinetic aspects of digoxin-specific Fab therapy in the management of digitalis toxicity. Clin. Pharmacokinetics. 28:483–493.CrossRefGoogle ScholarPubMed
Vázquez, H., Chávez-Haro, A., García-Ubbelohde, W., Mancilla-Nava, R., Paniagua-Solís, J., Alagón, A., and Sevcik, C.. 2005. Pharmacokinetics of a F(ab′)2 scorpion antivenom in healthy human volunteers. Toxicon. 46:797–805.CrossRefGoogle Scholar
Vellard, M. 2003. The enzyme as drug: application of enzymes as pharmaceuticals. Curr. Opin. Biotechnol. 14:444–450.CrossRefGoogle ScholarPubMed
Webster, R., Didier, E., Harris, P., Siegel, N., Stadler, J., Tilbury, L., and Smith, D.. 2007. PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies. Drug Metab. Disposition. 35:9–16.CrossRefGoogle ScholarPubMed
Wilkinson, I., Jackson, C.J.C., Lang, G.M., Holford-Stevens, V., and Sehon, A.H.. 1987. Tolerogenic polyethylene glycol derivatives of xenogeneic monoclonal immunoglobulins. Immunol. Letters. 15:17–22.CrossRefGoogle ScholarPubMed
Williams, L.E., Wu, A.M., Yazaki, P.J., Liu, A., Raubitschek, A.A., Shively, J.E., and Wong, T.Y.C.. 2001. Numerical selection of optimal tumour imaging agents with application to engineered antibodies. Canc. Biotherapy Radiopharmaceut. 16:25–35.CrossRefGoogle ScholarPubMed
Working, P.K., Newman, M.S., and Johnson, J.. 1997. Safety of poly(ethylene glycol) and poly(ethylene glycol) derivatives. In Poly(ethylene glycol) Chemistry and Biological Applications, edited by Harris, J.M., and Zalipsky, S. Washington: ACS Books, pp. 45–57.CrossRefGoogle Scholar
Wunderlich, D.A., Macdougall, M., Mierz, D.V., Toth, J.G., Buckholz, T.M., Lumb, K.J., and Vasavada, H.V.. 2007. Generation and characterisation of a monoclonal IgG antibody to polyethylene glycol. Hybridoma. 26:168–172.CrossRefGoogle Scholar
Xiong, C.Y., Natarjan, A., Shi, X.B., Denardo, G.L., and Denardo, S.J.. 2006. Development of tumour targeting anti-MUC-1 multimer: effects of di-scFv unpaired cysteine location on PEGylation and tumour binding. Prot. Eng. Des. Sel. 19:359–367.CrossRefGoogle Scholar
Yang, K., Basu, A., Wang, M., Chintala, R., Hsieh, M.C., Hua, J., Zhou, J., Li, M., Phyu, H., Petti, G., Phyi, H., Petti, G., Mendez, M., Janjua, H., Peng, P., Longley, C., Borowski, V., Mehlig, M., and Filpula, D.. 2003. Tailoring structure-function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation. Prot. Eng. 16:761–770.CrossRefGoogle ScholarPubMed
Yoshioka, Y., Tsutsumi, Y., Ikemizu, S., Yamamoto, Y., Shibata, H., Nishibata, T., Mukai, Y., Okamoto, T., Taniai, M., Kawamura, M., Abe, Y., Nakagawa, S., Nagata, S., Yamagata, Y., and Mayumi, T.. 2004. Optimal site-specific PEGylation of mutant TNF-α improves its antitumour potency. Biochem. Biophys. Res. Comms. 315:808–814.CrossRefGoogle Scholar
Zunino, F., Giuliani, F., Davi, G., Dasdis, T., and Gambetta, R.. 1982. Anti-tumour activity of daunorubicin linked to poly-L-aspartic acid. Interntl. J. Cancer. 30:465–470.CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×