CN-116688142-B - EGFR-targeted cyclized polypeptide-drug conjugate for tumor immunotherapy and application thereof

CN116688142BCN 116688142 BCN116688142 BCN 116688142BCN-116688142-B

Abstract

The invention discloses a targeted EGFR cyclized polypeptide-drug conjugate for tumor immunotherapy and application thereof, wherein the polypeptide drug conjugate comprises an EGFR targeted polypeptide and a first drug, wherein the EGFR targeted polypeptide comprises at least one cyclized structure, and a first drug Pt (IV) prodrug is used for forming a bridging unit of the at least one cyclized structure, wherein the Pt (IV) prodrug not only plays a role of a chemotherapeutic drug, but also serves as a bridging structure for restraining a polypeptide conformation, and the chemotherapeutic drug oxaliplatin and an IDO enzyme inhibitor NLG919 are combined to be used to have a synergistic effect of inducing immunogenic death. The conjugate can realize slow release of Oxaliplatin and NLG919 drugs in EGFR-targeted high-expression tumor cells, and has double synergistic effects of induction of immunogenic death (ICD) and inhibition of IDO.

Inventors

TIAN YUAN
QIU QIYUAN

Assignees

西南交通大学

Dates

Publication Date: 20260505
Application Date: 20230524

Claims (3)

1. An EGFR-targeted cyclized polypeptide-drug conjugate for use in tumor immunotherapy, wherein the EGFR-targeted cyclized polypeptide-drug conjugate has the structure shown in formula 1: formula 1.
2. Use of an EGFR-cyclized polypeptide-drug conjugate for use in tumor immunotherapy according to claim 1, wherein the tumor is selected from colon cancer or breast cancer.
3. The use according to claim 2, wherein the medicament is in the form of an injectable formulation, a tablet or a powder.

Description

EGFR-targeted cyclized polypeptide-drug conjugate for tumor immunotherapy and application thereof Technical Field The invention belongs to the field of biological medicine, and particularly relates to a targeted EGFR cyclized polypeptide-drug conjugate for tumor immunotherapy and application thereof. Background Peptide-drug conjugates (PDCs) as an emerging means of targeted drug delivery can improve efficacy and reduce side effects of cancer treatment, showing great potential in tumor immunotherapy. PDCs mainly comprise three basic components, polypeptide, drug and linker. The linkers in PDCs play a key role in the circulation time of the conjugate, the activity of the drug at the target site, and the release of the drug. The linkers commonly found in traditional PDCs can be broadly divided into 4 groups, enzyme cleavable linkers, acid cleavable linkers, reducible disulfide linkers, and non-cleavable linkers. Polypeptides used in PDCs are divided into two classes, cell penetrating peptides and cell targeting peptides. Cell penetrating peptides can interact with cell membranes and internalize by a variety of mechanisms, but this type of PDCs has limited application due to its low cell specificity. Cell-targeting peptides can selectively bind to over-expressed receptors present on target cells, delivering conjugated drugs to specific cells, but most cell-targeting peptides are chain linear peptides, resulting in their susceptibility to degradation in vivo and poor cell penetration. Whereas cyclized polypeptides are more stable than linear polypeptides, therefore cyclizing a linear polypeptide to a cyclized peptide or to a staple peptide with a higher helical structure helps to constrain the conformation of the polypeptide and improve its pharmacokinetic properties. At present, polypeptide cyclization mainly comprises main chain cyclization and side chain cyclization, wherein a common main chain cyclization method comprises the steps of oxidizing two sulfhydryl groups through oxidative coupling of cysteine to form disulfide bonds to form rings, introducing epsilon-azido lysine at one end of polypeptide and propargylglycine at the other end of polypeptide through cycloaddition reaction of azido and alkyne, and generating a cyclization group triazole connection group through Cu catalysis, and the side chain cyclization method mainly comprises the step of coupling side chains of two amino acids with a rigid small molecule. Drug molecules commonly used in tumor immunotherapy include immunogenic chemotherapeutics such as ARG inhibitor CB-1158, adenosine A2A receptor antagonist CPI-444, RORγt agonist LYC-55716, antibodies or chemicals reversing the tumor immunosuppressive microenvironment such as IDO enzyme inhibitor NLG919, but PDCs currently used in tumor immunotherapy are mainly limited to single drug studies or have unsatisfactory efficacy due to physicochemical properties of the drugs. Disclosure of Invention The invention provides a targeted EGFR cyclizing polypeptide-drug conjugate for tumor immunotherapy and application thereof, which cyclizes the targeted polypeptide by utilizing Pt (IV) prodrug Oxal (IV) with an axial ligand, on one hand, the Pt (IV) prodrug is used as a bridging structure for restricting the conformation of the targeted EGFR polypeptide, so that the stability and the cell penetrating capacity of the polypeptide are improved, on the other hand, after PDC drugs are cleaved in vivo by endogenous hydrolase, pt (IV) complexes are released, the Pt (IV) complexes are activated by reduction to become an active product Pt (II), and further, the combination use with IDO enzyme inhibitor (NLG 919) is realized by connecting IDO enzyme inhibitor on the targeted EGFR polypeptide in a breakable way, and the dual synergistic effect of immunogenic death (ICD) induction and IDO inhibition is realized. According to a first aspect of the present invention there is provided an EGFR-targeted cyclized polypeptide-drug conjugate for use in tumour immunotherapy, said polypeptide-drug conjugate comprising an EGFR-targeted polypeptide and a first drug, wherein said EGFR-targeted polypeptide comprises at least one cyclized structure and said first drug is for constituting a bridging unit of at least one cyclized structure. Epidermal Growth Factor Receptor (EGFR) is a cell-targeting peptide belonging to the ErbB family of receptor tyrosine kinases that converts various external stimuli into specific cellular responses upon kinase dependent activation by binding to ligands. In pathological settings, EGFR is a driver of tumorigenesis, which is mutated or overexpressed in a variety of cancers, and is a target widely adopted in current clinical therapies. Typically, in PDCs, the drug and linker are two different compounds that achieve cytotoxic and linking functions, respectively. In the invention, specific drug molecules are coupled with the polypeptide through structural modification, so that the drug molecules are use