CN-120590505-B - Recombinant complement protein and application thereof in preparation of anti-leukemia drugs

Abstract

The invention relates to a recombinant complement protein and application thereof in preparing an anti-leukemia drug, belonging to the technical field of biological medicine, and the invention discloses a single drug therapy, namely injection of recombinant C1QBP protein, which has remarkable effect in treating acute leukemia, can remarkably inhibit proliferation of leukemia cells in marrow, spleen and peripheral blood of a hematopoietic system, and simultaneously inhibit infiltration of leukemia cells in extramedullary organs (skin and the like), thereby reducing systemic tumor load and remarkably prolonging survival time of leukemia mice. The recombinant C1QBP protein is combined with a clinical first-line chemotherapy scheme, has a synergistic effect, has stronger effect of inhibiting leukemia cell proliferation than a single-use chemotherapy medicament, can remarkably prolong the survival time of leukemia mice, and plays a role in attenuation and synergy. The invention proves that the complement C1Q binding protein has the effect of treating leukemia for the first time, provides a preparation method and a combined administration scheme, and has higher clinical transformation prospect and application value.

Inventors

• LU YING
• YANG MENGYING
• HU LIHONG

Assignees

• 上海交通大学医学院附属新华医院

Dates

Publication Date

20260512

Application Date

20250606

Claims (3)

1. 1. Use of recombinant complement C1Q binding protein C1QBP in the manufacture of a medicament for the treatment of leukemia, said medicament inhibiting infiltration of leukemia cells into bone marrow and extramedullary tissues and organs.
2. 2. Use of a pharmaceutical composition comprising recombinant complement C1Q binding protein C1QBP and other chemotherapeutic agent which is daunorubicin for the preparation of a medicament for the synergistic treatment of leukemia.
3. 3. The use according to any one of claims 1-2, wherein the medicament is in the form of an injection.

Description

Recombinant complement protein and application thereof in preparation of anti-leukemia drugs Technical Field The invention relates to a recombinant complement protein and application thereof in preparation of anti-leukemia drugs, belonging to the technical field of biological medicine. Background Complement (complement) is a group of proteins consisting of 30 or more components that have enzymatic activity after activation, found in serum and tissue cells of healthy humans and animals. Complement is activated by classical, alternative and lectin pathways, forming the tapping complex complement-mediated cytolytic effects, an important component in the innate immune system. C1Q is a component of the innate immune complement classical pathway that initiates factor complement 1 (C1), which binds to an antigen-antibody complex and plays an important role in the complement classical activation pathway. Complement C1Q binding proteins, namely C1QBP (C1Q binding protein), are reported in the literature as p33, p32, gC1qR, HABP1 or C1QBP. C1QBP exists in a preprotein form containing 282 amino acid residues. After synthesis, 73 residues at the N-terminus are hydrolyzed to form the mature p33 protein containing 209 amino acids. The mature protein has high charge and acidity and isoelectric point of 4.15. The main ligands reported for the p33 proteins are C1q, hyaluronic acid, calreticulin, CD44, integrins, PKC, splicing factor ASF/SF2 and several microbial proteins. The functions involved in C1QBP include mitochondrial metabolism and kinetics, apoptosis, splicing, immune response, inflammation, and modulation of several cell signaling pathways. C1QBP (accession number of Gene ID 708 in NCBI, unilot protein database accession number Q07021). The typical intracellular localization of proteins is mitochondria, but can also be found in the cytoplasm, nucleus, cytoplasmic membrane, and can be secreted extracellularly. A series of studies have found that the protein is expressed on the surface of cell membranes. For example, the earliest identified purified p33 protein was obtained from Raji cell membrane fractions. Flow cytometry and confocal microscopy analysis using antibodies specific for C1QBP (mAb 60.11 or 74.5.2) showed that many cells, including Raji, a549, etc., cell membranes demonstrated a C1QBP specific signal. The subject group of the present application pre-analyzes RNA-seq sequencing data of large AML public databases (TCGA and BEAT dataset) and AML samples collected by the subject group, shows that C1QBP is highly expressed in AML (acute myelocytic leukemia, acute myeloid leukemia) and, in association with poor prognosis of disease, shows a significantly shortened survival of the highly expressed C1QBP group. Therefore, drugs developed targeting C1QBP have great application prospects in the treatment of AML. Leukemia is a malignant disease that originates from hematopoietic stem cells and is characterized by excessive proliferation and differentiation disorders of abnormal leukocytes (leukemia cells) in the bone marrow, resulting in the inhibition of normal hematopoietic function. Leukemia can be classified into acute leukemia (e.g., acute lymphoblastic leukemia ALL and acute myeloid leukemia AML) and chronic leukemia (e.g., chronic lymphoblastic leukemia CLL and chronic myeloid leukemia CML) according to the rate of disease progression and cell type. Its pathogenesis involves many factors such as genetic mutation, epigenetic change, abnormal signaling pathway, and microenvironment disorder. Common causative factors include radiation, chemical exposure, viral infection, genetic susceptibility, and the like. In terms of treatment, the therapeutic strategy for leukemia varies with type and stage. Acute leukemia is usually treated by high-intensity chemotherapy, targeted therapy, hematopoietic stem cell transplantation, etc., and immunotherapy (such as CAR-T cell therapy) has achieved remarkable effects in some ALL patients in recent years. Chronic leukemia is more dependent on targeted drugs (such as tyrosine kinase inhibitors TKI) and immunotherapy to control disease progression and to extend survival. Despite the continual progress in therapeutic approaches, some patients still face challenges such as drug resistance, recurrence, and treatment-related complications. Acute myelogenous leukemia (acute myeloid leukemia, AML) is a hematological malignancy that is a proliferation of naive granulocytes extremely due to a blocked differentiation of hematopoietic cells, accounting for about 80% of all acute leukemias. AML increases in incidence with age, and has a median age of 67 years and a incidence of 1/10 ten thousand under 30 years and up to 17/10 ten thousand over 75 years at diagnosis. With the acceleration of the aging process of the population in China, AML is becoming one of malignant tumors affecting the health of adults, especially the elderly in China. AML can be classified into several different subty