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CN-122011191-A - Anti-HER 3 antibody and anti-HER 3 antibody drug conjugate and medical application thereof

CN122011191ACN 122011191 ACN122011191 ACN 122011191ACN-122011191-A

Abstract

Anti-HER 3 antibodies and anti-HER 3 antibody drug conjugates and medical uses thereof are provided. Specifically, the antibody is an anti-HER 3 antibody, namely an anti-HER 3 antibody-drug conjugate shown as a general formula (Pc-L-Y-D), wherein Pc is an anti-HER 3 antibody, L, Y and n are defined in the specification.

Inventors

  • YANG YANG
  • YU JIA
  • TAO WEIKANG

Assignees

  • 苏州盛迪亚生物医药有限公司
  • 江苏恒瑞医药股份有限公司
  • 上海恒瑞医药有限公司

Dates

Publication Date
20260512
Application Date
20211014
Priority Date
20201014

Claims (19)

  1. 1. An isolated anti-HER 3 antibody, wherein the anti-HER 3 antibody has one or more of the following characteristics: a. The anti-HER 3 antibody binds to HER3 protein with an apparent affinity EC 50 of less than 0.5 nM, the apparent affinity EC 50 being determined by ELISA; b. The anti-HER 3 antibody binds to HER3 protein expressed by MCF7 cells with an apparent affinity EC 50 of less than 0.2 nM, said apparent affinity EC 50 being determined by FACS method; c. Preferably, when the anti-HER 3 antibody is tested by adopting DT3C endocytosis experiments, the IC 50 of the anti-HER 3 antibody is less than 2 nM; d. preferably, the FITC signal of the anti-HER 3 antibody is greater than 300 when the anti-HER 3 antibody is determined by a pHrodo antibody endocytosis assay.
  2. 2. The isolated anti-HER 3 antibody of claim 1, wherein the anti-HER 3 antibody comprises 1) HCDR1, HCDR2 and HCDR3 comprised in the heavy chain variable region of SEQ ID No. 7, and 2) LCDR1, LCDR2 and LCDR3 comprised in the light chain variable region of SEQ ID No. 8; Preferably, wherein the anti-HER 3 antibody comprises a heavy chain variable region and a light chain variable region, wherein: a. the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO. 9, SEQ ID NO. 10 and SEQ ID NO. 11 respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO. 12, SEQ ID NO. 13 and SEQ ID NO. 14 respectively; Wherein the CDR regions are defined according to the Chothia numbering convention, or B. The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO. 15, SEQ ID NO. 16 and SEQ ID NO. 17 respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO. 18, SEQ ID NO. 19 and SEQ ID NO. 20 respectively; Wherein the CDR regions are defined according to the IMGT numbering rules, or C. the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO. 21, SEQ ID NO. 22 and SEQ ID NO. 23 respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO. 24, SEQ ID NO. 25 and SEQ ID NO. 26 respectively; wherein the CDR regions are defined according to the Kabat numbering convention.
  3. 3. An isolated anti-HER 3 antibody, wherein the anti-HER 3 antibody comprises a heavy chain variable region and a light chain variable region, wherein: a. the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO. 9, SEQ ID NO. 10 and SEQ ID NO. 11 respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO. 12, SEQ ID NO. 13 and SEQ ID NO. 14 respectively; CDR regions as described above are defined according to the Chothia numbering convention, or B. The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO. 15, SEQ ID NO. 16 and SEQ ID NO. 17 respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO. 18, SEQ ID NO. 19 and SEQ ID NO. 20 respectively; CDR regions as described above are defined according to the IMGT numbering convention, or C. the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO. 21, SEQ ID NO. 22 and SEQ ID NO. 23 respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO. 24, SEQ ID NO. 25 and SEQ ID NO. 26 respectively; CDR regions as described above are determined according to the Kabat numbering convention.
  4. 4. The isolated anti-HER 3 antibody of any one of claims 1 to 3, wherein the anti-HER 3 antibody is a human antibody or antigen-binding fragment.
  5. 5. The isolated anti-HER 3 antibody of any one of claims 1 to 4, comprising a heavy chain variable region and a light chain variable region, wherein: The amino acid sequence of the heavy chain variable region has at least 90% sequence identity to SEQ ID No. 7 and/or the amino acid sequence of the light chain variable region has at least 90% sequence identity to SEQ ID No. 8; Preferably, the anti-HER 3 antibody comprises a heavy chain variable region and a light chain variable region, wherein: The amino acid sequence of the heavy chain variable region is shown as SEQ ID NO. 7, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO. 8.
  6. 6. The isolated anti-HER 3 antibody of any one of claims 1 to 5, comprising: A heavy chain having at least 85% sequence identity to SEQ ID NO. 27 and/or a light chain having at least 85% sequence identity to SEQ ID NO. 28; preferably, the anti-HER 3 antibody comprises: a heavy chain as shown in SEQ ID NO. 27 and a light chain as shown in SEQ ID NO. 28.
  7. 7. The isolated anti-HER 3 antibody of any one of claims 1 to 6, wherein the anti-HER 3 antibody has one or more of the following characteristics: a. The anti-HER 3 antibody binds to HER3 protein with an apparent affinity EC 50 of less than 0.5 nM, the apparent affinity EC 50 being determined by ELISA; b. The anti-HER 3 antibody binds to HER3 protein expressed by MCF7 cells with an apparent affinity EC 50 of less than 0.2 nM, said apparent affinity EC 50 being determined by FACS method; c. Preferably, when the anti-HER 3 antibody is tested by adopting DT3C endocytosis experiments, the IC 50 of the anti-HER 3 antibody is less than 2 nM; d. preferably, the FITC signal of the anti-HER 3 antibody is greater than 300 when the anti-HER 3 antibody is determined by a pHrodo antibody endocytosis assay.
  8. 8. An isolated anti-HER 3 antibody, wherein the antibody competes with the anti-HER 3 antibody of any one of claims 1 to 7 for binding to human HER3.
  9. 9. A nucleic acid molecule encoding the isolated anti-HER 3 antibody of any one of claims 1 to 8.
  10. 10. A host cell comprising the nucleic acid molecule of claim 9.
  11. 11. An immunoconjugate comprising the isolated anti-HER 3 antibody of any one of claims 1 to 8 and an effector molecule, wherein the effector molecule is conjugated to the anti-HER 3 antibody; Preferably, the effector molecule is selected from the group consisting of an anti-tumor agent, an immunomodulator, a biological response modifier, a lectin, a cytotoxic drug, a chromophore, a fluorophore, a chemiluminescent compound, an enzyme, a metal ion, and any combination thereof.
  12. 12. A method for immunodetection or determination of HER3, the method comprising the step of contacting the isolated anti-HER 3 antibody of any one of claims 1 to 8 with a subject or a sample from a subject.
  13. 13. An antibody-drug conjugate represented by the general formula (Pc-L a -Y-D) or a pharmaceutically acceptable salt thereof: Wherein, the Pc is the isolated anti-HER 3 antibody of any one of claims 1 to 8; m is an integer from 0 to 4; n is 1 to 10, n is a decimal or integer; R 1 is selected from halogen, haloalkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, and heteroaryl, R 2 is selected from hydrogen, halogen, haloalkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, and heteroaryl, or R 1 and R 2 together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl; W is selected from the group consisting of C 1-8 alkyl, C 1-8 alkyl-C 3-6 cycloalkyl and linear heteroalkyl of 1 to 8 chain atoms, said linear heteroalkyl of 1 to 8 chain atoms comprising 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein said C 1-8 alkyl, C 1-8 alkyl-C 3-6 cycloalkyl and linear heteroalkyl of 1 to 8 chain atoms are each independently optionally further substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, amino, alkyl, chloroalkyl, deuteroalkyl, alkoxy and cycloalkyl; L 2 is selected from -NR 4 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-、-NR 4 (CH 2 CH 2 O)p 1 CH 2 C(O)-、-S(CH 2 )p 1 C(O)- and a bond, wherein p 1 is an integer from 1 to 20; L 3 is a peptide residue consisting of 2 to 7 amino acid residues, wherein the amino acid residue is selected from the group consisting of amino acid residues formed by amino acids selected from phenylalanine, glycine, valine, lysine, citrulline, serine, glutamic acid and aspartic acid, and is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl; R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, and a hydroxyalkyl group; R 6 and R 7 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, and a hydroxyalkyl group.
  14. 14. The antibody-drug conjugate of the general formula (Pc-L a -Y-D) according to claim 13, or a pharmaceutically acceptable salt thereof, which is: Wherein: n is 1 to 8, n is a decimal or integer, preferably n is 3 to 8, n is a decimal or integer; HER3-29 is an anti-HER 3 antibody comprising a heavy chain as shown in SEQ ID NO. 27 and a light chain as shown in SEQ ID NO. 28.
  15. 15. A method for preparing the antibody-drug conjugate of the general formula (Pc-L a -Y-D) as defined in claim 13, or a pharmaceutically acceptable salt thereof, comprising the steps of: carrying out coupling reaction on Pc' and a compound shown in a general formula (L a -Y-D) to obtain a compound shown in the general formula (Pc-L a -Y-D); Wherein: Pc' is Pc reduced, pc, n, m, W, L 2 、L 3 、R 1 、R 2 、R 5 、R 6 and R 7 are as defined in claim 13.
  16. 16. A pharmaceutical composition comprising an isolated anti-HER 3 antibody according to any one of claims 1 to 8, or a nucleic acid molecule according to claim 9, or an antibody-drug conjugate according to claim 13 or 14, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.
  17. 17. Use of an isolated anti-HER 3 antibody according to any one of claims 1 to 8, or a nucleic acid molecule according to claim 9, or an antibody-drug conjugate according to claim 13 or 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for the treatment of a HER3 mediated disease or disorder.
  18. 18. Use of an isolated anti-HER 3 antibody according to any one of claims 1 to 8, or a nucleic acid molecule according to claim 9, or an antibody-drug conjugate according to claim 13 or 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for the treatment and/or prevention of a tumor; preferably, the tumor is selected from the group consisting of breast cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, prostate cancer, bladder cancer, colorectal cancer, head and neck squamous cell carcinoma, and melanoma.
  19. 19. A kit comprising the isolated anti-HER 3 antibody of any one of claims 1 to 8, or the nucleic acid molecule of claim 9, or the antibody-drug conjugate of claim 13 or 14, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16.

Description

Anti-HER 3 antibody and anti-HER 3 antibody drug conjugate and medical application thereof The application is a divisional application of patent application with the application number 202180054438.6 and the application date 2021, 10 months and 14 days, and the application and the creation of the patent application are named as 'anti-HER 3 antibody and anti-HER 3 antibody drug conjugate and medical application'. Technical Field The present disclosure relates to anti-HER 3 antibodies, anti-HER 3 antibody-irinotecan analog conjugates, methods of preparing the same, pharmaceutical compositions comprising the same, and uses thereof for preparing a medicament for treating HER3 mediated diseases or conditions, particularly for preparing anticancer medicaments. Background The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art. HER3 (EPIDERMAL GROWTH FACTOR RECEPTOR, erbB-3 or HER 3) is one of the members of the Epidermal Growth Factor Receptor (EGFR) family. This family includes HER1 (erbB 1, EGFR), HER2 (erbB 2, NEU), HER3 (erbB 3), and HER4 (erbB 4). These receptors each comprise 3 parts of an extracellular region comprising 4 domains, a transmembrane region and an intracellular region comprising 1 intracellular tyrosine kinase domain for signalling and 1 tail with tyrosine phosphorylating residues located in the cytosol. When the ligand binds to extracellular domains I and III, cell signaling is initiated. Under normal conditions, these receptors mediate cell division, migration, survival and organ development. When EGFR family members are mutated, the abnormal signaling they produce stimulates cell survival, which is associated with cancer progression. The rationale for HER3 receptor activation and physiological effects is similar to other family members, except that its ligands include neuregulin 1 (NRG-1) and neuregulin 2 (NRG-2), and HER3 does not form a homomer after activation, but only a heterodimer with EGFR or HER 2. HER3 exhibits high tyrosine phosphorylase activity in its intracellular domain portion during heterodimer formation, and it was found by structural analysis that HER3 intracellular domain has 6P 85 (PI-3K subunit) binding sites, and this specific structure determines that HER3 is able to recruit up to 6 PI-3K to the regulatory subunit sites upon interaction with the P85 regulatory subunit, thereby strongly activating PI-3K signaling pathways. In fact, HER3/HER2 dimer is the most active of the HER dimers. EGFR is widely distributed on the cell surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and the like. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. HER3 is highly expressed in various common malignancies, such as breast cancer, gastric cancer, ovarian cancer, prostate cancer, bladder cancer, colorectal cancer, head and neck squamous cell carcinoma, and melanoma, among others. Unlike EGFR gene mutation which causes high level expression or over activation, HER3 gene mutation rate is low, the high expression is mainly caused by mRNA transcription increase, so protein translation is increased, and high expression of HER3 which is often combined with HER2 high expression is closely related to the occurrence, progress and survival time of various tumors of a subject, so that anti-tumor drug research with HER3 as a target has important significance. Disclosure of Invention The present disclosure relates to anti-HER 3 antibodies, anti-HER 3 antibody-irinotecan analog conjugates, and uses thereof. The present disclosure provides an isolated anti-HER 3 antibody, wherein the anti-HER 3 antibody has one or more of the following characteristics: a. The anti-HER 3 antibody binds to HER3 protein with an apparent affinity EC 50 of less than 0.5 nM, the apparent affinity EC 50 being determined by ELISA; b. The anti-HER 3 antibody binds to HER3 protein expressed by MCF7 cells with an apparent affinity EC 50 of less than 0.2 nM, said apparent affinity EC 50 being determined by FACS method; c. the anti-HER 3 antibody is capable of being endocytosed by a cell expressing human HER 3. The present disclosure provides an isolated anti-HER 3 antibody, wherein the anti-HER 3 antibody has one or more of the following characteristics: a. The anti-HER 3 antibody binds to HER3 protein with an apparent affinity EC 50 of less than 0.5 nM, the apparent affinity EC 50 being determined by ELISA; b. The anti-HER 3 antibody binds to HER3 protein expressed by MCF7 cells with an apparent affinity EC 50 of less than 0.2 nM, said apparent affinity EC 50 being determined by FACS method; c. the anti-HER 3 antibody is capable of being endocytosed by a cell expressing human HER3, and has an IC 50 of less than 2 nM when the anti-HER 3 antibody is assayed by the method of test example 3; d. The anti-HER 3 antibody is capable of being end