Humanised antibodies to toll-like receptor 2 and uses thereof
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-039/395
C07K-016/28
C12P-021/00
C12N-015/09
C12N-015/13
C12N-015/63
C12N-005/10
C12N-005/12
출원번호
US-0382044
(2010-07-06)
등록번호
US-8734794
(2014-05-27)
우선권정보
IE-2009/0514 (2009-07-06)
국제출원번호
PCT/EP2010/059677
(2010-07-06)
§371/§102 date
20120315
(20120315)
국제공개번호
WO2011/003925
(2011-01-13)
발명자
/ 주소
Dellacasagrande, Jerome
출원인 / 주소
Opsona Therapeutics Limited
대리인 / 주소
Marshall, Gerstein & Borun LLP
인용정보
피인용 횟수 :
1인용 특허 :
7
초록▼
A fully humanized antibody having binding specificity to Toll-like Receptor 2 comprises a light chain and a heavy chain entirely comprised of amino acid sequence of human origin. The variable region of the light chain comprises an amino acid sequence which is substantially homologous with the sequen
A fully humanized antibody having binding specificity to Toll-like Receptor 2 comprises a light chain and a heavy chain entirely comprised of amino acid sequence of human origin. The variable region of the light chain comprises an amino acid sequence which is substantially homologous with the sequence of SEQ ID NO:1, while the variable region of the heavy domain comprises an amino acid sequence which is substantially homologous with the sequence of SEQ ID NO:4. Also provided are nucleic acids encoding such antibodies, as well as the use of the antibodies in medicine, in particular for the treatment of inflammatory and autoimmune diseases which are mediated by Toll-like Receptor 2 activation and signalling.
대표청구항▼
1. A neutralising antibody or an antigen binding portion thereof comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 or a sequence which has at least 90% amino acid sequence identity with SEQ ID NO: 1 and a heavy chain variable domain comprising the amino acid
1. A neutralising antibody or an antigen binding portion thereof comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 or a sequence which has at least 90% amino acid sequence identity with SEQ ID NO: 1 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:4 or a sequence which has at least 90% amino acid sequence identity with SEQ ID NO:4, wherein the antibody or antigen binding portion specifically binds to Toll-like Receptor 2 (TLR2) and wherein the antibody or antigen binding portion antagonises TLR2 independently of binding of the antibody or antigen binding portion to CD32, and wherein the light chain variable domain comprises CDR1, CDR2 and CDR3 of SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively, and the heavy chain variable domain comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively. 2. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1 wherein the variable domain of the light chain is joined to a Kappa constant domain. 3. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1 wherein the variable domain of the heavy chain is joined to at least one constant domain derived from an antibody of the subclass immunoglobulin G, isotype 4 (IgG4). 4. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 3 wherein amino acid residue 241 of a hinge region of the heavy chain is substituted from a serine residue to a proline residue (S241P). 5. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1 wherein the light chain comprises the amino acid sequence of SEQ ID NO:2. 6. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 5 wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:5. 7. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1 wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:5. 8. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1, wherein the antibody is a fully humanised antibody or an antigen binding portion thereof. 9. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1, wherein the antibody is an isolated antibody or an antigen binding portion thereof. 10. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1 wherein the antibody or antigen binding portion binds to human Toll-like Receptor 2 with a KD of 3×10−8 M or less. 11. An isolated nucleic acid molecule encoding the antibody or antigen binding portion thereof of claim 1. 12. An expression vector comprising the nucleic acid molecule of claim 11. 13. An isolated host cell comprising the expression vector of claim 12. 14. A method of producing a neutralising Toll-like Receptor 2 antibody or antigen binding portion thereof comprising culturing the host cell of claim 13 under appropriate conditions such that the antibody or antigen binding portion thereof is expressed and isolating the antibody or antigen binding portion thereof from the host cell or from cell culture supernatant. 15. A hybridoma cell line producing the antibody or antigen binding portion as claimed in claim 1. 16. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1 wherein the antibody or antigen binding portion has binding specificity to human Toll-like Receptor 2, mouse Toll-like Receptor 2 and monkey Toll-like Receptor 2. 17. The Toll-like Receptor 2 neutralising antibody or antigen binding portion as claimed in claim 1 wherein the light chain variable domain has the amino acid sequence of SEQ ID NO:1 and the heavy chain variable domain has the amino acid sequence of SEQ ID NO:4. 18. The neutralising antibody or antigen binding portion thereof as claimed in claim 1 wherein the light chain variable domain has the amino acid sequence of SEQ ID NO:1 or a sequence which has at least 95% amino acid sequence identity with SEQ ID NO:1 and the heavy chain variable domain has the amino acid sequence of SEQ ID NO:4 or a sequence which has at least 95% amino acid sequence identity with SEQ ID NO:4. 19. A method for treating an inflammatory, respiratory or autoimmune condition or disease which is mediated by Toll-like Receptor 2 activation, comprising administering in-vivo or ex-vivo, a therapeutically effective amount of the antibody or an antigen binding portion thereof according to claim 1 to a subject in need of such treatment. 20. The method as claimed in claim 19 wherein the inflammatory, respiratory or autoimmune condition or disease is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, allergic response, psoriasis, dermatitis, multiple sclerosis, atherosclerosis, ischemia reperfusion injury, ischemia reperfusion resulting from organ transplantation, ocular disease, uveitis, age-related macular degeneration, renal inflammation and diabetes. 21. A method for treating or preventing sepsis, comprising administering a therapeutically effective amount of the antibody or antigen binding portion according to claim 1 to a subject in need of such treatment. 22. An isolated monoclonal antibody, or antigen binding portion thereof, which binds an epitope on human Toll-like Receptor 2 with a KD of 3×10−8 M or less and which mediates Toll-like Receptor 2 antagonism independently of binding of the antibody or antigen binding portion to CD32 (Fc gamma receptor II), wherein the epitope is recognised by a reference antibody, wherein the reference antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:1. 23. The isolated monoclonal antibody or antigen binding portion thereof as claimed in claim 22 wherein the reference antibody comprises the heavy chain of SEQ ID NO:5 and the light chain of SEQ ID NO:2. 24. The isolated monoclonal antibody; or antigen binding portion thereof as claimed in claim 22 wherein the antibody or antigen binding portion has binding specificity to human Toll-like Receptor 2, mouse Toll-like Receptor 2 and monkey Toll-like Receptor 2.
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이 특허에 인용된 특허 (7)
Espevik,Terje; Sundan,Anders, Antibody against the human toll-like receptor 2 (tlr2) and uses thereof.
Griffiths, Andrew David; Hoogenboom, Hendricus Renerus Jacobus Mattheus; Marks, James David; McCafferty, John; Winter, Gregory Paul; Grigg, Geoffrey Walter, Production of anti-self antibodies from antibody segment repertoires and displayed on phage.
Griffiths, Andrew David; Hoogenboom, Hendricus Renerus Jacobus Mattheus; Marks, James David; McCafferty, John; Winter, Gregory Paul; Grigg, Geoffrey Walter, Production of anti-self bodies from antibody segment repertories and displayed on phage.
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