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CN-122028932-A - Use of bispecific antibody in preparation of medicine for treating cancer

CN122028932ACN 122028932 ACN122028932 ACN 122028932ACN-122028932-A

Abstract

There is provided the use of a bispecific antibody in the manufacture of a medicament for the treatment of cancer, in particular in the manufacture of a medicament for the treatment of advanced solid tumors.

Inventors

  • MA XIAOYING
  • QIAN HUI
  • ZHOU YUANFENG
  • CHEN LILI

Assignees

  • 上海翰森生物医药科技有限公司
  • 常州恒邦药业有限公司
  • 百欧恩泰(珠海)医药研发有限公司

Dates

Publication Date
20260512
Application Date
20240927
Priority Date
20230928

Claims (20)

  1. Use of a bispecific antibody comprising a first antibody or antigen-binding fragment directed against a first target c-Met and a second antibody or antigen-binding fragment directed against a second target EGFR in the manufacture of a medicament for the prevention or treatment of cancer; Wherein the first antibody or antigen binding fragment comprises HCDR1 as shown in SEQ ID NO. 01, HCDR2 as shown in SEQ ID NO. 02, HCDR3 as shown in SEQ ID NO. 03, and LCDR1 as shown in SEQ ID NO. 04, LCDR2 as shown in SEQ ID NO. 05, LCDR3 as shown in SEQ ID NO. 06; Wherein the second antibody or antigen binding fragment comprises HCDR1 as shown in SEQ ID NO:09, HCDR2 as shown in SEQ ID NO:10, HCDR3 as shown in SEQ ID NO:11, and LCDR1 as shown in SEQ ID NO:12, LCDR2 as shown in SEQ ID NO:13, LCDR3 as shown in SEQ ID NO: 14.
  2. The use of claim 1, wherein the c-Met binding domain of the bispecific antibody is a Fab region formed from a first heavy chain and a first light chain, the EGFR binding domain is a Fab region formed from a second heavy chain and a second light chain, and the first heavy chain and the second heavy chain combine to form a heterodimeric Fc region.
  3. Use of a bispecific antibody pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of cancer, characterized in that the bispecific antibody pharmaceutical composition comprises the bispecific antibody of the use of claim 1 or2 and one or more pharmaceutically acceptable excipients, diluents or carriers.
  4. The use according to any one of claims 1 to 3, wherein the bispecific antibody or bispecific antibody pharmaceutical composition is used in combination with an EGFR inhibitor for the preparation of the medicament.
  5. The use according to claim 4, wherein the EGFR inhibitor is selected from one or more of almitinib (almonertinib), erlotinib (erlotinib), gefitinib (gefitinib), bei Fu tinib (befotertinib), octreotide (osimertinib), vomittinib (furmonertinib), soritinib (oritinib), reezetinib (Rezetinib), ivertinib (Avitinib), olmesatinib (olmutinib) and Luo Xiti ni (rociletinib), preferably from almitinib (almonertinib) or octreotinib (osimertinib).
  6. The use of any one of claims 1 to 5, wherein the first antibody or antigen binding fragment comprises a heavy chain variable region as shown in SEQ ID NO:07 or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:07 and a light chain variable region as shown in SEQ ID NO:08 or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:08, and the second antibody or antigen binding fragment comprises a heavy chain variable region as shown in SEQ ID NO:15 or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:15 and a light chain variable region as shown in SEQ ID NO:16 or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16.
  7. The use of any one of claims 1 to 6, wherein the first antibody or antigen binding fragment comprises a heavy chain as shown in SEQ ID No. 21 or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 21 and a light chain as shown in SEQ ID No. 22 or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 22, and the second antibody or antigen binding fragment comprises a heavy chain as shown in SEQ ID No. 23 or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 23 and a light chain as shown in SEQ ID No. 24 or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 24.
  8. The use according to any one of claims 1 to 7, wherein the bispecific antibody, bispecific antibody pharmaceutical composition and EGFR inhibitor are contained as active ingredients in separate formulations, respectively, and are administered simultaneously, concurrently, sequentially, consecutively, alternately or separately.
  9. The use according to any one of claims 1 to 8, wherein the cancer is selected from solid tumors, preferably advanced solid tumors.
  10. The use according to any one of claims 1 to 9, wherein the cancer is a c-Met or/and EGFR expressing cancer.
  11. The use according to claim 10, wherein the cancer expressing c-Met or/and EGFR is mediated by wild-type EGFR, EGFR activating mutation, EGFR gene amplification, elevated levels of circulating HGF, wild-type c-Met, c-Met activating mutation, c-Met gene amplification, or mutant KRAS, preferably by EGFR activating mutation, met gene amplification.
  12. The use of claim 11, wherein the EGFR activating mutation comprises at least one mutation ：L718Q、L718V、G719A、G719S、G719C、G719D、L858R、L858P、L861Q、G724S、E746K、L747S、E749Q、A750P、A755V、V765M、C797S、S768I or T790M substitution selected from the group consisting of; deletion of E746-A750, deletion of R748-P753, insertion of Ala (A) between M766 and A767, insertion of Ser, val and Ala (SVA) between S768 and V769, insertion of Asn and Ser (NS) between P772 and H773, deletion of one or more amino acids in EGFR exon 19, insertion of one or more amino acids in EGFR exon 19, deletion of one or more amino acids in EGFR exon 20, between M766 and A767, between A767 and V768, between S768 and V769, between V769 and D770, between D770 and N771, between N771 and P772, between P772 and H773, between H773 and V774, between V774 and C775.
  13. The use according to any one of claims 1 to 12, wherein the cancer is selected from the group consisting of epithelial cell cancer, breast cancer, ovarian cancer, lung cancer, rectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharynx cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, oesophageal cancer, vaginal cancer, endometrial cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer or melanoma, preferably lung cancer or liver cancer.
  14. The use of claim 12, wherein the cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous carcinoma, large cell lung cancer, small cell lung cancer, lung sarcoidosis, or hepatocellular carcinoma (HCC); Preferably, the EGFR activating mutation is a T790M/L858R, D770-N771 ins_SVD, del19/T790M/C797S or 19 exon deletion.
  15. The use of claim 14, wherein the cancer is non-squamous non-small cell lung cancer.
  16. The use according to any one of claims 4 to 15, wherein the EGFR inhibitor is administered in a dose of 10-500mg, preferably 10-200mg, more preferably 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg or 200mg.
  17. The use of any one of claims 4-16, wherein the EGFR inhibitor is administered twice daily, once daily or once daily for three days, preferably once daily or once daily for two days.
  18. The use according to any one of claims 3 to 17, wherein the bispecific antibody pharmaceutical composition is in a unit concentration of about 1mg/mL to about 100mg/mL, preferably about 5mg/mL to about 50mg/mL, more preferably about 10mg/mL to about 30mg/mL, e.g. 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50mg/mL; Preferably, the bispecific antibody pharmaceutical composition further comprises a buffer and sucrose; More preferably, the buffer is citric acid-sodium citrate at a concentration of 5-150mM, e.g., 10mM, and sucrose at a concentration of 20-60mg/mL, e.g., 40mg/mL.
  19. The use of any one of claims 3-18, wherein the bispecific antibody pharmaceutical composition is in a format of 10ml:10mg to 10ml:1000mg, preferably 10ml:100mg to 10ml:500mg, more preferably 10ml:100mg, 10ml:200mg, 10ml:300mg, 10ml:400mg or 10ml:500mg per dose.
  20. The use according to any one of claims 1 to 19, wherein the bispecific antibody or bispecific antibody pharmaceutical composition is administered in a dose of about 100mg to about 5000mg, preferably 400mg to about 2000mg, more preferably 400mg, 800mg, 1000mg, 1200mg, 1400mg, 1600mg, 1800mg or 2000mg.

Description

Use of bispecific antibody in preparation of medicine for treating cancer The present application claims priority from China patent application 2023112834484 with the application date 2023/9/28. The present application incorporates the entirety of the above-mentioned chinese patent application. Technical Field The invention belongs to the field of medicines, and relates to application of a bispecific antibody in preparation of a medicine for treating cancers, wherein the bispecific antibody is a medicine for simultaneously inhibiting human epidermal growth factor receptor and tyrosine kinase Met double targets, and based on a unique structure and a novel action mechanism, the bispecific antibody has potential to realize clinical benefit which is difficult to realize by single medicine or combined medicine. Background EGFR is one of the members of the human epidermal growth factor receptor (HER) family, widely distributed on the surface of tissues or cells of epithelial, mesenchymal and neuronal origin. Under physiological conditions, it can promote cell differentiation, proliferation, migration and survival after binding to its ligand (e.g., epidermal growth factor EGF). Under pathological conditions, EGFR is taken as a pro-oncogene, and the occurrence and development of tumors can be promoted by means of gene mutation, up-regulation of expression and the like. Common EGFR gene mutation sites are exons 18-21, mainly Exon 19 deletion (Exon 19 del), exon 21L 858R point mutation (L858R), exon 20 insertion mutation (Exon 20 ins), and the like. EGFR mutations or overexpression have a high incidence in NSCLC (50% mutation), head and neck cancer (80% overexpression), colon cancer (25% mutation) and breast cancer (11% overexpression/mutation), and several EGFR-targeting drugs have been validated for clinical effectiveness in the above indications. The MET gene belongs to a protooncogene, codes for a cell interstitial epidermal transforming factor (c-MET), also called Hepatocyte Growth Factor Receptor (HGFR), and the c-MET/HGFR belongs to a Receptor Tyrosine Kinase (RTK) family, is a transmembrane tyrosine kinase receptor, and can induce the dimerization of MET and the phosphorylation of a substrate thereof after being combined with a ligand Hepatocyte Growth Factor (HGF), so as to activate a downstream signal path and participate in the processes of regulating proliferation, differentiation, migration, angiogenesis and the like of cells. The c-MET pathway is closely related to EGFR resistance. MET gene expression bypasses the inhibited EGFR phosphoryl kinase pathway, providing a bypass pathway by activating the ERBB3 and PI3K/AKT pathway downstream of MET. MET activates and promotes downstream signal transduction through this bypass pathway, avoids apoptosis caused by EGFR TKI, and promotes tumor cell proliferation, ultimately resulting in EGFR TKI resistance. Therefore, it is highly necessary to inhibit both the EGFR and c-MET pathway to overcome EGFR TKI resistance caused by MET pathway activation, which provides a theoretical basis for c-MET pathway inhibition in combination with EGFR pathway inhibition for the treatment of advanced solid tumors. EGFR Exon 20ins are insensitive to the existing EGFR TKIs of one to three generations due to the special mutation structure, and have poor effects similar to chemotherapy and immunotherapy. The first line standard treatment recommended by the 2022 CSCO guidelines remains platinum-based chemotherapy. For patients with advanced solid tumors that are resistant to EGFR targets due to activation of the c-MET pathway, no standard treatment is currently available. Finding an effective treatment is therefore an urgent clinical need. Disclosure of Invention The invention provides an application of a bispecific antibody specifically binding to c-Met and EGFR in preparing a medicament for preventing or treating cancer. The invention also provides application of a pharmaceutical composition of the bispecific antibody specifically binding to c-Met and EGFR in preparing medicines for preventing or treating cancers. The invention also provides a bispecific antibody specifically binding to c-Met and EGFR, or a pharmaceutical composition of the bispecific antibody, in combination with an EGFR inhibitor, for use in the manufacture of a medicament for preventing or treating cancer. In some embodiments, the EGFR inhibitor is selected from erlotinib (erlotinib), gefitinib (gefitinib), bei Fu tinib (befotertinib), aonitinib (osimertinib), amotinib (almonertinib), vomittinib (furmonertinib), aorittinib (oritinib), reezetinib (Rezetinib), ivertinib (Avitinib), olmitinib (olmutinib), luo Xiti ni (rociletinib), preferably amotinib (almonertinib), aonititinib (osimertinib). In some embodiments, the bispecific antibody or bispecific antibody pharmaceutical composition described above, the EGFR inhibitor, respectively, is contained as an active ingredient in different formulations and is administer