The invention discloses nucleotide of fusion protein for coding neutrophil elastase and application of the nucleotide. A nucleotide sequence for coding the fusion protein is as shown in SEQ ID NO. 8; the nucleotide sequence of mRNA (messenger ribonucleic acid) for coding the fusion protein is as shown in SEQ ID NO. 12; the fusion protein comprises an optimized human neutrophilelastase (ELANE) fragment and an optimized human alpha2-macroglobulin (A2M) fragment. The mRNA preparation which is encapsulated by the nano-lipid particles and is used for coding the wild type ELANE can achieve a tumor elimination effect only by complex intratumor injection. According to the mRNA preparation which is encapsulated by the nano-lipid particles and is used for coding the ELANE fusion protein, tumor elimination in a mouse body can be realized only through intramuscular injection administration, the operation is simpler and more convenient, and the mRNA preparation is beneficial to treatment of scattered and tiny tumor focuses in the body.
The present invention relates to proteinprodrug constructs, e.g., protein fusion constructs, comprising complement 3 and pregnancy zone protein-like alpha-2-macroglobulin domain (CPAMD)-containing proteins (e.g., A2M) and one or more drugs, and acting as protease activatable prodrugs. The invention also relates to the release mechanism of the CPAMD protein and the development of multispecific drugs, such as bispecific drugs.
The present invention relates to a protein fusion construct comprising a proteinprodrug construct, for example, a complement 3- and pregnancy-related protein-like alpha-2-macroglobulin domain-containing (CPAMD) protein (e.g., A2M) and one or more drugs, which functions as a protease-activatable prodrug. The present invention further relates to the release mechanism from the CPAMD protein and the development of multispecific drugs such as bispecificity.
Provided are modified alpha-2-macroglobulin (A2M) proteins with altered binding to clearance receptors such as LRP1 and GRP78, compositions comprising protein complexes of the modified A2M proteins with serineprotease proteins such as porcine pancreatic elastase (PPE), compositions comprising protein complexes of alpha-2-macroglobulin-like protein 1 (A2ML1) with serineprotease proteins, and related methods of use and manufacture for treating diseases such as cancers.