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Bispecific domain antibodies targeting serum albumin and GLP-1 or PYY

A serum albumin and GLP-1 technology, applied in the field of bispecific domain antibodies targeting serum albumin and GLP-1 or PYY, can solve the problem of not producing long-acting active GLP-1

Inactive Publication Date: 2008-02-20
DORMANTIS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, despite these efforts, no long-acting active GLP-1

Method used

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  • Bispecific domain antibodies targeting serum albumin and GLP-1 or PYY
  • Bispecific domain antibodies targeting serum albumin and GLP-1 or PYY
  • Bispecific domain antibodies targeting serum albumin and GLP-1 or PYY

Examples

Experimental program
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preparation example Construction

[0134] Preparation of immunizing antigens, polyclonal and monoclonal antibody production can be performed using any suitable technique. Various methods have been described. (See, for example, Kohler et al., Nature, 256:495-497 (1975) and Eur.J.Immunol.6:511-519 (1976); Milstein et al., Nature 266:550-552 (1977); Koprowski et al., U.S. Patent No. 4,172,124; Harlow, E. and D. Lane, 1988, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory: Cold Spring Harbor, NY); Current Protocols In Molecular Biology, Vol.2 (Supplement 27, Summer' 94), in Ausubel, F.M. et al. (John Wiley & Sons: New York, NY), Chapter 11, (1991).). Generally, when monoclonal antibodies are desired, hybridomas are produced by fusing appropriate cells from an immortal cell line (eg, a myeloma cell line such as SP2 / 0, P3X63Ag8.653, or heteromyeloma) with antibody-producing cells. Antibody-producing cells can be obtained from the peripheral blood or, preferably, the spleen or lymph nodes of humans, h...

Embodiment 1

[0352] Example 1 Selection of Domain Antibodies Binding to Mouse, Rat and Human Serum Albumin

[0353] This example illustrates a method for making single domain antibodies (dAbs) directed against serum albumin. A selection of dAbs directed against mouse serum albumin (MSA), human serum albumin (HSA) and rat serum albumin (RSA) is described.

[0354] dAbs directed against mouse serum albumin were selected as described in WO2004 / 003019A2. Three human phage display antibody libraries were used. Each library is based on V H (V3-23 / DP47 and J H 4b) or V κ (o12 / o2 / DPK9 and J κ 1) Single person frame, V H and V κ Side chain diversity encoded by NNK codons introduced in the complementarity determining fragments (CDR1, CDR2 and CDR3).

[0355] Library 1 (V H )

[0356] Diversity positions are: H30, H31, H33, H35, H50, H52, H52a, H53, H55, H56, H58, H95, H97, H98

[0357] Library size: 6.2×10 9

[0358] Library 2 (V H ):

[0359] The diversity positions are: H30, H31, H3...

Embodiment 2

[0377] Example 2. Formatting Anti-Serum Albumin Antibody as a Fusion to IL-1 Receptor Antagonist (IL-1ra)

[0378] This example describes a method for making a fusion protein comprising IL-1ra and a dAb that binds serum albumin. Two fusions were formed, one with the dAb N-terminus of IL-1ra (MSA16IL1-ra) and one with the dAb C-terminus of IL-1ra (IL1-ra MSA 16). The sequence and vector of the fusions are shown in Figures 2C and 2D. A control fusion that did not bind MSA was also generated, the sequence of which is shown in Figure 2E.

[0379] KINERET (anakina, Amgen) has a short half-life of 4-6 hours and the recommended dosing regimen calls for daily injections. This regimen resulted in injection site reactions within 14-28 days in 71% of cases. Therefore, a form of human IL-1ra with a longer serum half-life would be beneficial and allow for increased efficacy and less frequent dosing. These are desirable characteristics for pharmacology.

[0380] clone

[0381] Briefly...

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Abstract

Drug fusions and conjugates comprising an incretin therapeutic or diagnostic agent fused or conjugated to an antigen-binding fragment of an antibody that binds serum albumin. Conjugates and fusions have longer half-lives in vivo compared to unconjugated or unfused therapeutic or diagnostic agents.

Description

[0001] related application [0002] This application claims the benefit of U.S. Provisional Patent Application No. 60 / 632,361 filed December 2, 2004 and GB Patent Application No. 0511019.2. The entire teaching of the above application is hereby incorporated by reference. Background of the invention [0003] Many drugs have activity that can be used for therapeutic and / or diagnostic purposes, but are of limited value because they are rapidly eliminated from the body when administered. For example, many therapeutically active polypeptides are rapidly cleared from circulation by the kidneys. Therefore, in order to obtain the desired therapeutic effect, large doses must be administered. There is a need for improved therapeutic and diagnostic agents with improved pharmacokinetic properties. [0004] One such class of drugs with a short half-life in vivo or in the systemic circulation is the incretin hormones, such as glucagon-like peptide 1 or peptide YY. [0005] Glucagon-like...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/46C07K16/44A61K47/48A61P1/00A61P3/10
CPCC07K2319/31C07K2318/20C07K2319/00C07K14/7155C07K2317/569A61K47/48415C07K14/70578A61K39/3955C07K16/44A61K47/48538A61K38/00C07K2318/10C12N15/62A61K47/6811A61K47/6843A61P1/00A61P1/04A61P1/14A61P25/28A61P3/04A61P3/06A61P43/00A61P9/00A61P9/10A61P9/12A61P3/10A61K47/50
Inventor S·霍尔姆斯L·J·霍尔特L·S·耶斯珀斯I·M·汤林森
Owner DORMANTIS LTD
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