Chimeric human-mouse IgG antibodies with shuffled constant region exons demonstrate that multiple domains contribute to in vivo half-life

Lionel S. Zuckier, Chee J. Chang, Matthew D. Scharff, Sherie L. Morrison

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Structural features that determine the differing rates of immunoglobulin catabolism are of great relevence to the engineering of immunologically active reagents. Sequences in the C(H)2 and C(H)3 region of IgG have been shown to regulate the rate of clearance through their interaction with FcRn. In an attempt to probe additional structural features that regulate antibody half-life, we have investigated two families of chimeric antibodies, composed of identical murine heavy and light antidansyl variable regions joined to human κ light-chains and wild-type or shuffled human IgG heavy-chain constant regions. These antibodies were iodinated, and their clearance was studied in severe combined immunodeficient mice hosts by whole-body radioactivity measurements. Clearances of the wild-type and recombinant antibodies were biphasic. In a panel of immunoglobulins derived from IgG2 and IgG3, as successive domains were varied from γ2 to γ3, β-phase half-life gradually decreased from 337.0 h to 70.6 h. Statistical analysis suggested that the composition of each of the three domains affected half- life, and no single region of the molecule by itself determined the rate of clearance. In the second panel of immunoglobulins derived from IgG1 and IgG4, the construct with the amino terminus portion of the molecule derived from IgG4, joined within the C(H)2 domain to the COOH terminus portion of IgG1, had a half-life paradoxically greater than either IgG1 or IgG4 (P < 0.012). All four IgG1/IgG4 constructs demonstrated presence of the concentration catabolism phenomenon, which is a unique hallmark of immunoglobulin catabolism. The contribution of all three constant region domains to immunoglobulin half-life may be due to distant conformational effects in addition to direct binding to protective receptors, and emphasizes the importance of distant sequences on the rate of immunoglobulin catabolism. Interesting possibilities regarding mechanisms controlling immunoglobulin metabolism are raised by the hybrid γ41 molecule with a half-life greater than either parental immunoglobulin. Understanding the relationships between the structure of these molecules and their clearance rate will further our ability to produce immunoglobulins with improved pharmacokinetic properties.

Original languageEnglish (US)
Pages (from-to)3905-3908
Number of pages4
JournalCancer Research
Volume58
Issue number17
StatePublished - Sep 1 1998

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Half-Life
Exons
Immunoglobulin G
Antibodies
Immunoglobulins
Light
SCID Mice
Radioactivity
Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chimeric human-mouse IgG antibodies with shuffled constant region exons demonstrate that multiple domains contribute to in vivo half-life. / Zuckier, Lionel S.; Chang, Chee J.; Scharff, Matthew D.; Morrison, Sherie L.

In: Cancer Research, Vol. 58, No. 17, 01.09.1998, p. 3905-3908.

Research output: Contribution to journalArticle

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