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CN-121975014-A - Anti-DLL 3 antibodies and related products and uses thereof

CN121975014ACN 121975014 ACN121975014 ACN 121975014ACN-121975014-A

Abstract

The invention discloses an anti-DLL 3 antibody and a related product and application thereof, and relates to the field of antibodies. The anti-DLL 3 antibody with obvious effect is screened, and the antibody not only can be subjected to high-specificity binding with a DLL3 target spot, but also has excellent binding affinity. The anti-DLL 3 antibody is used as an antigen binding domain, and is further prepared into CAR-T cells, and experiments prove that the CAR-T cells show potent and stable anti-tumor activity, can specifically identify and kill DLL3 positive tumor cells, and effectively inhibit tumor growth and proliferation. The anti-DLL 3 antibody and the corresponding CAR-T cell can be widely applied to the preparation of medicaments for preventing or treating DLL3 positive tumors, provide a new targeted therapy selection for DLL3 positive tumor patients, and have important clinical application value and broad industrialization prospect.

Inventors

  • LU QIZHONG
  • TONG AIPING
  • CHEN YONGDONG
  • LI HEXIAN
  • DU HAOTIAN
  • LI JIA
  • ZHU ZHIXIONG
  • NIE CHUNLAI

Assignees

  • 天府锦城实验室(前沿医学中心)

Dates

Publication Date
20260505
Application Date
20260130

Claims (10)

  1. 1. An anti-DLL 3 antibody or antigen binding fragment thereof, which comprises HCDR1, HCDR2 and HCDR3 in the heavy chain variable region as shown in SEQ ID NO. 4, and LCDR1, LCDR2 and LCDR3 in the light chain variable region as shown in SEQ ID NO. 7.
  2. 2. The antibody or antigen-binding fragment thereof of claim 1, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are defined by any one of Kabat, chothia, IMGT, abM or Contact; optionally, the amino acid sequences of the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are shown as SEQ ID NO 1-3, SEQ ID NO 5, KVS and SEQ ID NO 6 in sequence.
  3. 3. The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region; The amino acid sequence of the heavy chain variable region is shown as SEQ ID NO. 4, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO. 7; Optionally, the antibody further comprises a constant region; Alternatively, the constant region is of a species source of bovine, equine, porcine, ovine, caprine, rat, mouse, canine, camel, feline, rabbit, donkey, deer, mink, chicken, duck, goose, or human; Optionally, the heavy chain constant region is selected from the group consisting of a heavy chain constant region of any of IgG1, igG2, igG3, igG4, igA, igM, igE, and IgD, and/or a light chain constant region is selected from the group consisting of kappa-type or lambda-type light chain constant regions; alternatively, the antigen binding fragment comprises any one of Fab, fab ', F (ab') 2 , scFv, fv; alternatively, when the antigen binding fragment is an scFv, the amino acid sequence of the scFv is shown in SEQ ID NO. 8.
  4. 4. An antibody conjugate, characterized in that the antibody or the antigen binding fragment thereof according to any one of claims 1-3; Optionally, the antibody conjugate further comprises a label, purification tag and/or solid phase carrier conjugated to the anti-DLL 3 antibody or antigen binding fragment thereof.
  5. 5. A chimeric antigen receptor, wherein the antigen binding domain of the chimeric antigen receptor comprises the anti-DLL 3 antibody or antigen binding fragment thereof of any one of claims 1-3.
  6. 6. A CAR-T cell comprising the chimeric antigen receptor of claim 5.
  7. 7. A reagent or kit comprising the anti-DLL 3 antibody or antigen binding fragment thereof according to any one of claims 1 to 3, or the antibody conjugate according to claim 4, or the chimeric antigen receptor according to claim 5 or the CAR-T cell according to claim 6.
  8. 8. An immunoconjugate or pharmaceutical composition comprising an antibody or antigen-binding fragment thereof against DLL3 according to any one of claims 1 to 3, or an antibody conjugate according to claim 4, or a chimeric antigen receptor according to claim 5, or a CAR-T cell according to claim 6.
  9. 9. Use of an anti-DLL 3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, or an antibody conjugate according to claim 4, or a chimeric antigen receptor according to claim 5, or a CAR-T cell according to claim 6, in the manufacture of a medicament for the prevention or treatment of DLL3 positive tumors.
  10. 10. The use of claim 9 wherein the DLL3 positive tumor comprises at least one of small cell lung cancer, neuroendocrine prostate cancer, melanoma, gastrointestinal pancreatic neuroendocrine tumor, metastatic castration prostate cancer, large cell neuroendocrine cancer, small cell bladder cancer, pulmonary neuroendocrine tumor, or glioblastoma multiforme.

Description

Anti-DLL 3 antibodies and related products and uses thereof Technical Field The present invention relates to the field of antibodies, in particular to anti-DLL 3 antibodies and related products and uses thereof. Background Lung cancer is a major cause of cancer-related death worldwide, with Small Cell Lung Cancer (SCLC) accounting for about 15% -20%. SCLC is a high-grade neuroendocrine tumor closely related to smoking, and common symptoms include cough, dyspnea, hemoptysis, and the like. Most patients have distant metastasis at the time of diagnosis, the prognosis is extremely poor, the existing chemotherapy and radiotherapy are effective in the early stage, but the curative effect is short, the median survival time of the patients with metastasis is only about 1 year, and the patients with limitation are usually less than 2 years. Therefore, there is a great clinical interest in exploring SCLC from epidemiology, pathogenesis, to new therapeutic approaches, etc. Delta-like ligand 3 (DLL 3), which belongs to the Notch ligand family, is a type I single transmembrane protein. The structure includes an extracellular DSL domain, six EGF-like repeats, a transmembrane region, and an intracellular domain, wherein the DSL domain is responsible for binding to Notch receptors. DLL3 is hardly expressed in normal tissues, but is significantly highly expressed on the surface of tumor cells in more than 80% of SCLC patients, especially in the neuroendocrine subtype, making it a very potential therapeutic target. Targeting strategies for DLL3, such as antibody drug conjugates, bispecific T cell cement, and CAR-T therapies are under investigation. For example, the bispecific antibody taratuzumab targeting DLL3 has shown an objective remission rate of about 40% in recurrent SCLC, with partial patient remission duration exceeding 6 months. High expression of DLL3 is also associated with poor prognosis, possibly as a biomarker for predictive therapeutic response. In conclusion, the specific high expression of DLL3 in SCLC provides important basis for targeted therapy, and further researches on biological functions and regulation mechanisms of the DLL3 are expected to bring new therapeutic directions to SCLC patients. Chimeric antigen receptor T cells (CAR-T) are a breakthrough technology in the field of tumor immunotherapy. Through genetic engineering, the chimeric receptor capable of specifically recognizing tumor antigens is expressed on the surface of T cells, so that tumor cells are precisely targeted and eliminated. When the CAR-T cells are combined with tumor antigens, the CAR-T cells are activated and proliferated, and the CAR-T cells kill tumors by releasing toxic substances such as perforin, granzyme and the like and cytokines such as interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and the like. The technology has excellent curative effect in the treatment of various malignant tumors of the blood system, not only innovates the treatment mode of the hematological tumor, but also promotes the development of other immunotherapy. Currently, the in-research drug treatment forms of targeting DLL3 for SCLC treatment comprise monoclonal antibodies, ADC, diabodies, polyclonal antibodies, CAR-T, CAR-NK and the like, but the curative effect is still to be improved. In view of this, the present invention has been made. Disclosure of Invention The present invention aims to provide antibodies against DLL3 and related products and uses thereof. The invention is realized in the following way: In a first aspect, embodiments of the present invention provide an anti-DLL 3 antibody or antigen binding fragment thereof comprising HCDR1, HCDR2 and HCDR3 in the heavy chain variable region of SEQ ID NO. 4 and LCDR1, LCDR2 and LCDR3 in the light chain variable region of SEQ ID NO. 7. In a second aspect, embodiments of the present invention provide an antibody conjugate comprising an antibody or antigen-binding fragment thereof according to the previous embodiments. In a third aspect, embodiments of the present invention provide a chimeric antigen receptor whose antigen binding domain comprises an antibody or antigen binding fragment thereof against DLL3 as described in the previous embodiments. In a fourth aspect, embodiments of the invention provide a CAR-T cell comprising a chimeric antigen receptor as described in the previous embodiments. In a fifth aspect, embodiments of the invention provide a reagent or kit comprising an anti-DLL 3 antibody or antigen binding fragment thereof as described in the previous embodiments, or an antibody conjugate as described in the previous embodiments, or a chimeric antigen receptor as described in the previous embodiments, or a CAR-T cell as described in the previous embodiments. In a sixth aspect, embodiments of the invention provide an immunoconjugate or pharmaceutical composition comprising an antibody or antigen binding fragment thereof against DLL3 as described in the previous embodiments, or an a