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CN-115819588-B - Novel anti-CD 19 antibodies

CN115819588BCN 115819588 BCN115819588 BCN 115819588BCN-115819588-B

Abstract

The present invention provides antibodies against CD19 or antigen binding fragments thereof, isolated polynucleotides encoding the same, pharmaceutical compositions comprising the same, and uses thereof.

Inventors

  • LI JING
  • LIU JIEYING

Assignees

  • 上海药明生物技术有限公司

Dates

Publication Date
20260512
Application Date
20180920
Priority Date
20170921

Claims (20)

  1. 1. An isolated anti-CD 19 antibody or antigen-binding fragment thereof, comprising: a) A heavy chain variable region comprising HCDR1 as shown in SEQ ID NO.1, HCDR2 as shown in SEQ ID NO. 2 and HCDR3 as shown in SEQ ID NO. 3, and a kappa light chain variable region comprising LCDR1 as shown in SEQ ID NO. 4, LCDR2 as shown in SEQ ID NO. 5 and LCDR3 as shown in SEQ ID NO. 6; b) A heavy chain variable region comprising HCDR1 as shown in SEQ ID NO. 7, HCDR2 as shown in SEQ ID NO. 8 and HCDR3 as shown in SEQ ID NO. 9, and a kappa light chain variable region comprising LCDR1 as shown in SEQ ID NO. 10, LCDR2 as shown in SEQ ID NO. 11 and LCDR3 as shown in SEQ ID NO. 12; c) A heavy chain variable region comprising HCDR1 as shown in SEQ ID NO:136, HCDR2 as shown in SEQ ID NO:2 and HCDR3 as shown in SEQ ID NO:3, and a kappa light chain variable region comprising LCDR1 as shown in SEQ ID NO:137, LCDR2 as shown in SEQ ID NO:138 and LCDR3 as shown in SEQ ID NO:139, or D) Heavy chain variable regions comprising HCDR1 as shown in SEQ ID NO. 7, HCDR2 as shown in SEQ ID NO. 140 and HCDR3 as shown in SEQ ID NO. 9, and kappa light chain variable regions comprising LCDR1 as shown in SEQ ID NO. 10, LCDR2 as shown in SEQ ID NO. 11 and LCDR3 as shown in SEQ ID NO. 12.
  2. 2. The antibody or antigen-binding fragment thereof according to claim 1, comprising a heavy chain variable region selected from the group consisting of SEQ ID NO. 94, SEQ ID NO. 98, SEQ ID NO. 124 and SEQ ID NO. 128.
  3. 3. The antibody or antigen-binding fragment thereof of claim 1, comprising a kappa light chain variable region selected from the group consisting of SEQ ID NO:96, SEQ ID NO:100, SEQ ID NO:126 and SEQ ID NO: 130.
  4. 4. The antibody or antigen binding fragment thereof of claim 1, comprising a heavy chain variable region having an amino acid sequence with at least 97% sequence identity to SEQ ID NO. 124, and a kappa light chain variable region having an amino acid sequence with at least 97% sequence identity to SEQ ID NO. 126.
  5. 5. The antibody or antigen-binding fragment thereof according to claim 1, comprising a heavy chain variable region having an amino acid sequence with a substitution and/or deletion of not more than 3 amino acid residues in the framework region relative to SEQ ID NO:124, and a kappa light chain variable region having an amino acid sequence with a substitution and/or deletion of not more than 3 amino acid residues in the framework region relative to SEQ ID NO: 126.
  6. 6. The antibody or antigen binding fragment thereof of any one of the preceding claims, comprising: a) A heavy chain variable region comprising SEQ ID NO. 94, and a kappa light chain variable region comprising SEQ ID NO. 96; b) A heavy chain variable region comprising SEQ ID NO. 98, and a kappa light chain variable region comprising SEQ ID NO. 100; c) A heavy chain variable region comprising SEQ ID NO. 124, and a kappa light chain variable region comprising SEQ ID NO. 126, or D) A heavy chain variable region comprising SEQ ID NO. 128, and a kappa light chain variable region comprising SEQ ID NO. 130.
  7. 7. The antibody or antigen-binding fragment thereof of claim 1, further comprising an immunoglobulin constant region.
  8. 8. The antibody or antigen-binding fragment thereof of claim 7, wherein the immunoglobulin constant region is a constant region of IgG.
  9. 9. The antibody or antigen binding fragment thereof of claim 8, wherein the constant region of IgG is a constant region of human IgG 1.
  10. 10. The antibody or antigen-binding fragment thereof of claim 1, which is a humanized antibody.
  11. 11. The antibody or antigen binding fragment thereof of claim 1, which is a diabody (diabody), scFv dimer, bsFv, dsFv, (dsFv) 2 , dsFv-dsFv ', fv fragment, fab ', F (ab ') 2 , or ds diabody (ds diabody).
  12. 12. The antibody or antigen-binding fragment thereof of claim 1, which is bispecific.
  13. 13. The antibody or antigen binding fragment thereof of claim 1, which is linked to one or more conjugates.
  14. 14. The antibody or antigen binding fragment thereof of claim 13, wherein the conjugate is a toxin, radioisotope, lanthanide, luminescent label, fluorescent label, or enzyme substrate label.
  15. 15. The antibody or antigen-binding fragment thereof of claim 13, wherein the conjugate is a chemotherapeutic agent.
  16. 16. The antibody or antigen binding fragment thereof of claim 1, which is capable of specifically binding to CD19 of human or monkey origin.
  17. 17. The antibody or antigen binding fragment thereof of claim 1, which is capable of specifically binding to human CD19 expressed on cells with a K D value of no more than 5 x 10 -9 M, said K D value determined by flow cytometry.
  18. 18. The antibody or antigen binding fragment thereof of claim 1, which is capable of specifically binding to human CD19 expressed on cells with an EC 50 value of no more than 0.9nM or no more than 1nM, as determined by flow cytometry.
  19. 19. The antibody or antigen binding fragment thereof of claim 1, which is capable of specifically binding to cynomolgus monkey CD19 expressed on cells with an EC 50 value of no more than 3nM, as determined by flow cytometry.
  20. 20. The antibody or antigen binding fragment thereof of claim 1, which is capable of internalizing by a CD19 expressing cell with an EC 50 value of no more than 50pM, said EC 50 value being determined by the Fab-Zap method.

Description

Novel anti-CD 19 antibodies The application is a divisional application of Chinese application patent application with the application number 201811100667.3 and the application date 2018, 9, 20 and the application name of 'novel anti-CD 19 antibody'. The original application claims priority from international application with application number PCT/CN2017/102631, with application date 2017, 9, 21. Technical Field The present invention relates generally to novel anti-CD 19 antibodies and uses thereof. Background CD19 (cluster of differentiation 19) is a cell surface receptor expressed on the surface of B cells with a specific structure, including but not limited to all subtypes of B cell lymphomas, from indolent to aggressive, and B cell chronic lymphocytic leukemia and non-T cell acute lymphocytic leukemia, pre-B cells, B cells in early stages of development (i.e., immature B cells), mature B cells undergoing terminal differentiation to plasma cells, and malignant B cells. CD19 is expressed by most pre-B cell Acute Lymphoblastic Leukemias (ALL), non-Hodgkin's lymphoma, B cell Chronic Lymphoblastic Leukemias (CLL), lymphoblastic leukemias, hairy cell leukemias, general acute lymphoblastic leukemias, and some zero acute lymphoblastic leukemias (Nadle et al, J.Immunol.,131:244-250 (1983), loken et al, blood,70:1316-1324 (1987), uckun et al, blood,71:13-29 (1988), anderson et al, 1984.Blood,63:1424-1433 (1984), scheuermann, leuk.Lymphoma,18:385-397 (1995)). CD19 expression on plasma cells has further shown that it can be expressed on differentiated B cell tumors, such as multiple myeloma, plasmacytoma, waldenstein tumors (Grossbard et al, br. J. Haemato., 102:509-15 (1998); treon et al, semin. Oncol.,30:248-52 (2003)). CD19 is also one of the multiple targets recommended for immunotherapy. Unlike CD20 (another B cell surface receptor), CD19 is thought to be expressed at higher levels when bound to anti-CD 19 antibodies and internalized by the cell. There remains a need for new anti-CD 19 antibodies, in particular anti-CD 19 antibodies with superior internalizing ability as well as high binding affinity. Brief description of the invention The articles "a," "an," and "the" are used throughout this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. For example, "an antibody" refers to one antibody or more than one antibody. The present application provides novel anti-CD 19 monoclonal antibodies, their amino acid and nucleotide sequences, and uses thereof. In one aspect, the application provides an isolated antibody or antigen binding fragment thereof comprising one or more (e.g., 1, 2, or 3) heavy chain Complementarity Determining Region (CDR) sequences ：SEQ ID NO:1、2、3、7、8、9、13、14、15、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、43、44、45、136、140 and 141 selected from the group consisting of, and/or one or more (e.g., 1, 2, or 3) kappa light chain CDR sequences selected from the group consisting of SEQ ID NOs 4, 5, 6, 10, 11, 12, 16, 17, 18, 40, 41, 42, 137, 138, and 139. In certain embodiments, the antibody or antigen binding fragment thereof comprises 1, 2, or 3 heavy chain CDR sequences that have at least 80% (e.g., at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to a sequence set forth in SEQ ID NO:1、2、3、7、8、9、13、14、15、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、43、44、45、136、140 or 141. In certain embodiments, the antibody or antigen binding fragment thereof comprises 1, 2, or 3 light chain CDR sequences that have at least 80% (e.g., at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOs 4,5, 6, 10, 11, 12, 16, 17, 18, 40, 41, 42, 137, 138, or 139. In certain embodiments, an antibody or antigen binding fragment thereof of the application comprises a heavy chain variable region selected from the group consisting of: a) A heavy chain variable region comprising 1, 2 or3 CDR sequences selected from SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3; b) A heavy chain variable region comprising 1, 2 or 3 CDR sequences selected from the group consisting of SEQ ID No. 7, SEQ ID No. 8 and SEQ ID No. 9; c) A heavy chain variable region comprising 1,2 or 3 CDR sequences selected from SEQ ID No. 13, SEQ ID No. 14 and SEQ ID No. 15; d) A heavy chain variable region comprising 1,2 or 3 CDR sequences selected from SEQ ID No. 19, SEQ ID No. 20 and SEQ ID No. 21; e) A heavy chain variable region comprising 1,2 or 3 CDR sequences selected from the group consisting of SEQ ID No. 22, SEQ ID No. 23 and SEQ ID No. 24; f) A heavy chain variable region comprising 1,2 or 3 CDR sequences selected from the group consisting of SEQ ID No. 25, SEQ ID No. 26 and SEQ ID No. 27; g) A heavy chain variable region comprising 1,2 or 3 CDR sequences selected from the group consisting of SEQ ID No. 28, SEQ ID No. 29 and SEQ ID No. 30; h) A heavy chain variable region compr