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Chimeric Human-Mouse IgG Antibodies with Shuffled Constant Region Exons Demonstrate that Multiple Domains Contribute to in Vivo Half-Life

Departments of Nuclear Medicine [L. S. Z.], Epidemiology and Biostatistics [C. J. C.], and Cell Biology [M. D. S.], Albert Einstein College of Medicine, Bronx, New York 10461, and Department of Microbiology and Molecular Genetics and the Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California 90095 [S. L. M.]

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_H2 and C_H3 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 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 ₂ to ₃, ß-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_H2 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 ₄/₁ 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.

¹ To whom requests for reprints should be addressed, at Department of Nuclear Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann Building, Room 121, Bronx, NY 10461.

Received 9/26/97. Accepted 7/ 2/98.

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