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Humanised antibodies

a technology of humanized antibodies and antibodies, applied in the field of humanised antibody molecules, can solve the problems of inherently limited use of rodent mabs as therapeutic agents in humans, and affecting the effect of immune respons

Inactive Publication Date: 2005-06-09
UCB PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0103] By examination of available X-ray structures we have identified a number of residues which may have an effect on n

Problems solved by technology

However, such uses, especially in therapy, were hindered until recently by the polyclonal nature of natural immunoglobulins.
Since most available MAbs are of rodent origin, they are naturally antigenic in humans and thus can give rise to an undesirable immune response termed the HAMA (Human Anti-Mouse Antibody) response.
Therefore, the use of rodent MAbs as therapeutic agents in humans is inherently limited by the fact that the human subject will mount an immunological response to the MAb and will either remove it entirely or at least reduce its effectiveness.
In practice, MAbs of rodent origin may not be used in patients for more than one or a few treatments as a HAMA response soon develops rendering the MAb ineffective as well as giving rise to undesirable reactions.
(7) and (8)] was not sufficient to provide satisfactory antigen binding activity in the CDR-grafted product.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

CDR-Grafting of OKT3

Material and Methods

[0127] 1. Incoming Cells

[0128] Hybridoma cells producing antibody OKT3 were provided by Ortho (seedlot 4882.1) and were grown up in antibiotic free Dulbecco's Modified Eagles Medium (DMEM) supplemented with glutamine and 5% foetal calf serum, and divided to provide both an overgrown supernatant for evaluation and cells for extraction of RNA. The overgrown supernatant was shown to contain 250 ug / mL marine IgG2a / kappa antibody. The supernatant was negative for murine lambda light chain and IgG1, IgG2b, IgG3, IgA and IgM heavy chain. 20 mL of supernatant was assayed to confirm that the antibody present was OKT3.

2. Molecular Biology Procedures

[0129] Basic molecular biology procedures were as described in Maniatis et al (ref. 9) with, in some cases, minor modifications. DNA sequencing was performed as described in Sanger et al (ref. 11) and the Amersham International Plc sequencing handbook. Site directed mutagenesis was as described in Kra...

example 2

CDR-Grafting of a Murine Anti-CD4 T Cell Receptor Antibody, OKT4A

[0224] Anti OKT4A CDR-grafted heavy and light chain genes were prepared, expressed and tested substantially as described above in Example 1 for CDR-grafted OKT3. The CDR grafting of OKT4A is described in detail in Ortho patent application PCT / GB 90 . . . of even date herewith entitled “Humanised Antibodies”. The disclosure of this Ortho patent application PCT / GB 90 . . . is incorporated herein by reference. A number of CDR-4rafted OKT4 antibodies have been prepared. Presently the CDR-grafted OKT4A of choice is the combination of the grafted light chain LCDR2 and the grafted heavy chain HCDR10.

The Light Chain

[0225] The human acceptor framework used for the grafted light chains was RE1. The preferred LCDR2 light chain has human to mouse changes at positions 33, 34, 38, 49 and 89 in addition to the structural loop CDRs. Of these changed positions, positions 33, 34 and 89 fall within the preferred extended CDRs of the...

example 3

CDR-Grafting of an Anti-Mucin Specific Murine Antibody, B72.3

[0233] The cloning of the genes coding for the anti-mucin specific murine monoclonal antibody B72.3 and the preparation of B72.3 mouse-human chimeric antibodies has been described previously (ref. 13 and WO 89 / 01783). CDR-grafted versions of B72.3 were prepared as follows.

(a) B72.3 Light Chain

[0234] CDR-grafting of this light chain was accomplished by direct transfer of the murine CDRs into the framework of the human light chain RE1.

[0235] The regions transferred were:

CDR NumberResidues124-34250-56390-96

[0236] The activity of the resulting grafted light chain was assessed by co-expression in COS cells, of genes for the combinations: [0237] B72.3 cH / B72.3 cL [0238] and B72.3 cH / B72.3 gL

[0239] Supernatants were assayed for antibody concentration and for the ability to bind to microtitre plates coated with mucin. The results obtained indicated that, in combination with the B72.3 cH chain, B72.3 cL and B72.3 gL had si...

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Abstract

CDR-grafted antibody heavy and light chains comprise acceptor framework and donor antigen binding regions, the heavy chains comprising donor residues at at least one of positions (6, 23) and / or (24, 48) and / or (49, 71) and / or (73, 75) and / or (76) and / or (78) and (88) and / or (91). The CDR-grafted light chains comprise donor residues at at least one of positions (1) and / or (3) and (46) and / or (47) or at at least one of positions (46,48, 58) and (71). The CDR-grafted antibodies are preferably humanised antibodies, having non human, e.g. rodent, donor and human acceptor frameworks, and may be used for in vivo therapy and diagnosis. A generally applicable protocol is disclosed for obtaining CDR-grafted antibodies.

Description

FIELD OF THE INVENTION [0001] The present invention relates to humanised antibody molecules, to processes for their production using recombinant DNA technology, and to their therapeutic uses. [0002] The term “humanised antibody molecule” is used to describe a molecule having an antigen binding site derived from an immunoglobulin from a non-human species, and remaining immunoglobulin-derived parts of the molecule being derived from a human immunoglobulin. The antigen binding site typically comprises complementarity determining regions (CDRs) which determine the binding specificity of the antibody molecule and which are carried on appropriate framework regions in the variable domains. There are 3 CDRs (CDR1, CDR2 and CDR3) in each of the heavy and light chain variable domains. [0003] In the description, reference is made to a number of publications by number. The publications are listed in numerical order at the end of the description. BACKGROUND OF THE INVENTION [0004] Natural immuno...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61KA61K38/00A61K49/00A61P37/00C07K14/435C07K14/52C07K14/525C07K14/725C07K16/00C07K16/18C07K16/24C07K16/28C07K16/42C07K16/46C07K19/00C12NC12N5/10C12N15/09C12N15/13C12P21/00C12P21/02C12P21/08C12QC12R1/91G01N33/53G01N33/577
CPCA61K38/00C07K14/7051C07K16/18C07K16/241C07K16/2803C07K2319/02C07K16/2812C07K16/461C07K16/465C07K2317/24C07K2319/00C07K16/2809A61P37/00C07K16/28
Inventor ADAIR, JOHNATHWAL, DILJEETEMTAGE, JOHN
Owner UCB PHARMA SA
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