Compositions targeting endothelial cells and uses thereof

A composition comprising a first binder connected to a second binder via a first linker, wherein the first binder specifically binds to a protein expressed on an endothelial cell.

A composition comprising a binder connected to a payload via a first linker, wherein the binder specifically binds to a protein expressed on an endothelial cell.

The composition of any one of the preceding claims, wherein the protein is an organ-restricted endothelial cell protein or tissue-specific endothelial cell protein.

The composition of any one of the preceding claims, wherein the protein has low expression levels on non-tumor endothelial cells.

The composition of any one of the preceding claims, wherein the protein is not expressed in circulating blood cells.

The composition of any one of the preceding claims, wherein the protein has greater expression levels on tumor endothelial cells than on non-tumor endothelial cells.

The composition of any one of the preceding claims, wherein the protein is encoded by a gene selected from the group consisting of genes set forth in Tables 1-3.

The composition of any one of the preceding claims, wherein the protein is encoded by a gene selected from VMP1, LAPTM5, EVL, PCDH17, ARRDC3, PMEPA-1, MYOF, MMP14, or PLEKHO1.

The composition of any one of the preceding claims, wherein the protein is PMEPA-1.

The composition of any one of the preceding claims, wherein the binder, first binder, and/or the second binder are an antibody or an antigen-binding fragment thereof.

The composition of any one of the preceding claims, wherein the binder, first binder, and/or the second binder

• (a) is a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific antibody, a multispecific antibody, a grafted antibody, a human antibody, a humanized antibody, a synthetic antibody, a chimeric antibody, a camelized antibody, a single-chain Fvs (scFv), a single chain antibody, a Fab fragment, a F(ab′)2 fragment, a Fd fragment, a Fv fragment, a single-domain antibody, a diabody, a fragment comprised of only a single monomeric variable domain, disulfide-linked Fvs (sdFv), an intrabody, an anti-idiotypic (anti-Id) antibody, a nanobody, or an antigen-binding fragment thereof;
• or
• (b) an aptamer, a dendrimer, a peptide, RNAi, siRNA, shRNA, miRNA.

The composition of any one of the preceding claims, wherein the binder, first binder, and/or the second binder are a nanobody, a single chain variable fragment (scFv), a single-chain antibody, a single-domain antibody, a diabody, a Fab fragment, or a combination thereof.

The composition of any one of the preceding claims, wherein the binder, first binder, and/or the second binder are a nanobody.

The composition of any one of the preceding claims, wherein the binder, first binder, and/or the second binder are is an endothelial cell specific antibody or an antigen-binding fragment thereof.

The composition of any one of the preceding claims, wherein the binder, first binder, and/or the second binder are is an anti-PMEPA-1 antibody or an antigen-binding fragment thereof.

A cell comprising a first binder that specifically binds to a protein expressed on an endothelial cell.

The cell of 168 or 169, wherein the polypeptide linker comprises (G4S)n, (SG4)n, G4(SG4)n or G2(SG2)n, wherein n is selected from 1 to 10.

An engineered immune cell comprising:

• (a) a first polynucleotide that encodes a first binder that specifically binds to a protein expressed on an endothelial cell;
• and
• (b) a second polynucleotide that encodes a chimeric antigen receptor (CAR).

The engineered immune cell of 202 or 203, wherein the co-stimulatory domain is 41-BB or OX40.