Characterization of human monoclonal antibodies directed against hepatitis B surface antigen

Ehrlich, Paul H.; Moustafa, Zeinab A.; Justice, James C.; Harfeldt, K. Elisabeth; Kelley, Robin L.; Östberg, Lars

doi:10.3233/hab-1992-3101

Cited by 25 publications

(22 citation statements)

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Section: Engineered Antibodies With Longer Serum Half-lives 6215supporting

confidence: 86%

“…Finally, the mean elimination (␤-phase) half-life (t1 ⁄2 ) was ϳ1.8-fold longer for the M428L mutant (642 Ϯ 205 h) and ϳ1.9-fold longer for the T250Q/M428L mutant (652 Ϯ 28 h; p ϭ 0.029) compared with wild-type OST577-IgG 2 M3 (351 Ϯ 121 h) ( Table I). The elimination half-life for wild-type OST577-IgG 2 M3 in this study is similar to that for OST577-IgG 1 (324 Ϯ 85 h) in a previous PK study in rhesus monkeys (27).Although there is an indication from the CL and AUC parameters that the T250Q/M428L mutant may have increased serum persistence compared with the M428L mutant, this difference may not be significant. Since the elimination half-lives of the two mutants appear similar, it is possible that a maximal increase in serum persistence has been achieved in rhesus monkeys with these mutants.…”

supporting

confidence: 80%

“…IgG Mutagenesis, Expression, and Purification-The light and heavy chain cDNAs from a trioma cell line expressing the human anti-hepatitis B virus (HBV) antibody OST577 (27) were cloned by PCR. The light and heavy chain V-genes were converted by PCR into mini-exons and subcloned, respectively, into pV2, a derivative of pVk (28) containing the human 2 constant region, and the M3 variant of pVg2.D.Tt (26).…”

Section: Methodsmentioning

confidence: 99%

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Engineered Human IgG Antibodies with Longer Serum Half-lives in Primates

Hinton

Johlfs

Xiong

et al. 2004

Journal of Biological Chemistry

246

189

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Antibody therapy is coming of age, with 15 monoclonal antibodies approved for therapeutic use in the United States and many others currently undergoing clinical trials (1). The advent of antibody engineering over the past two decades has contributed to the recent clinical success of therapeutic antibodies. The development of chimeric (2) and humanized (3) antibodies not only reduced the potent immunogenicity of rodent antibodies in humans but also improved the serum halflives and efficacy of such therapeutics compared with rodent antibodies. Phage display (4) and other display technologies have led to the ability to increase the affinity of antibodies for their target antigens. More recently, antibody engineering has been used to modify the effector functions of antibodies by altering their binding to C1q (5) and various Fc␥ receptors (6).The neonatal Fc receptor (FcRn) 1 is a heterodimer that comprises a transmembrane ␣ chain with structural homology to the extracellular domains of the ␣ chain of major histocompatibility complex class I molecules, and a soluble light chain consisting of ␤2-microglubulin (␤2m) (7). FcRn mediates both transcytosis of maternal IgG to the fetus or neonate and IgG homeostasis in adults (8). Evidence for the latter role initially came from studies indicating an unusually short serum halflife for IgG antibodies in ␤2m-deficient mice (9 -11). This observation led to the generation of mutant mouse hinge-Fc fragments with enhanced binding to FcRn and increased serum persistence in mice (12). Recently, several studies have identified human IgG 1 mutants with enhanced FcRn binding (6, 13), although no improvement in the serum half-lives of these mutants was observed in mice (13) or reported in primates.The binding of IgG to FcRn is sharply pH-dependent; IgG binds to FcRn under mildly acidic conditions and is released under slightly basic conditions (14). It has been hypothesized that pinocytosed IgG antibodies are captured by FcRn in acidified endosomes, rescued from degradation in lysosomes, recycled back to the cell surface, and returned to the circulation (8). Mutagenesis studies have identified both the mouse (15, 16) and human (17) Fc residues believed to be important in mediating pH-dependent binding. The results of the mutagenesis studies are consistent with the interpretation of a crystallographic study of the Fc⅐FcRn interaction (18). In the current study, molecular modeling was used to identify residues in the human IgG Fc near the FcRn binding site that, when mutated, might alter binding to FcRn without affecting the pH dependence of this interaction. Following exhaustive mutagenesis at these positions, several IgG 2 mutants were identified with improved binding to FcRn at pH 6.0 that retained the property of pH-dependent release. A pharmacokinetics study in rhesus monkeys showed that two mutant IgG 2 antibodies with increased FcRn binding affinity had considerably longer serum half-lives than the wild-type antibody. EXPERIMENTAL PROCEDURESMolecular Modeling-Molecular models o...

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Section: Engineered Antibodies With Longer Serum Half-lives 6215supporting

confidence: 86%

supporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Engineered Human IgG Antibodies with Longer Serum Half-lives in Primates

Hinton

Johlfs

Xiong

et al. 2004

Journal of Biological Chemistry

246

189

View full text Add to dashboard Cite

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“…This has suggested the possibility of using monoclonal antibodies directed against the a determinant for the immunoprophylaxis or treatment of HBV infection and disease. Recently, one such antibody, human monoclonal antibody SDZ OST 577 (8,9), was administered to a small number of orthotopic liver transplant patients who underwent transplantation for end-stage liver disease associated with chronic HBV infection in an attempt to prevent recurrence of hepatitis B (10). Although the results suggest that multiple doses of this monoclonal antibody could prevent recurrent hepatitis B in some liver transplant patients, the protective efficacy of the antibody has not been evaluated in a systematic manner.…”

mentioning

confidence: 99%

Markedly prolonged incubation period of hepatitis B in a chimpanzee passively immunized with a human monoclonal antibody to the a determinant of hepatitis B surface antigen.

Ogata

Östberg

Ehrlich

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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The protective efficacy of a human monoclonal antibody directed against the a determinant of hepatitis B virus (HBV) surface antigen was studied in a chimpanzee. A single high dose of 5 mg/kg (body weight) of monoclonal antibody SDZ OST 577 was intravenously administered to a chimpanzee, followed by intravenous challenge with 103-5 chimpanzee infectious doses of a wild-type HBV, the MS-2 strain (ayw subtype). The passively acquired antibody to HBV surface antigen could be detected for 40 weeks. Serum HBV DNA tested by a "nested" polymerase chain reaction assay was negative through the 36th week after virus challenge but became positive by the 38th week. The chimpanzee subsequently developed acute hepatitis B -1 year after challenge. The nucleotide sequence of the a determinant of the surface gene of the replicated virus was identical with that of the inoculated wild-type virus. Thus, a human monoclonal antibody directed against the a determinant ofHBV surface antigen delayed but did not prevent experimental infection of HBV and hepatitis in the chimpanzee. Our results indicate an incomplete ability of this antibody to protect against HBV infection in vivo after a single infusion.

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“…Fax j31 10 436 5145. e-mail heijtink!viro.fgg.eur.nl deficiency virus types 1 and 2, and hepatitis C virus has stimulated the introduction and application of (human) monoclonal antibodies (Ehrlich et al, 1992).…”

Section: Introductionmentioning

confidence: 99%