Immunotherapeutic molecules and uses
The invention provides molecule comprising: (i) a targeting moiety capable of directly or indirectly targeting to unwanted cells, and (ii) a further moiety that has a masked immune cell binding region so as to prevent binding of the further moiety to an immune cell, wherein the masked immune cell binding region is capable of being selectively unmasked when the molecule is in the vicinity of the unwanted cells so as to allow binding of the further moiety to an immune cell.
1. A composition for redirecting T cells to tumour cells comprising:
(i) a targeting moiety capable of targeting to tumour cells wherein the targeting moiety is an antibody or an antigen-binding fragment thereof that specifically binds to an antigen expressed by the tumour cells and wherein the targeting moiety is not masked, and
(ii) at least one further moiety that has a masked CD3- or T cell receptor (TCR)-binding region so as to prevent binding of the further moiety to a T cell,
wherein the masked CD3- or TCR-binding region is capable of being selectively unmasked by cleavage of at least one protease cleavage site when the molecule is in the vicinity of the tumour cells so as to allow binding of the further moiety to a T cell and wherein the further moiety is a scFv antibody in which the linker that joins the heavy chain variable domain (VH) and light chain variable domain (VL) is of insufficient length, optionally a peptide linker of 14 or less amino acids, to allow pairing of the VH and VL domains such that the scFv antibody cannot bind to the T cell, and wherein, when in the vicinity of the tumour cells, pairing of the VH and VL domains occurs by selectively cleaving one or more cleavage sites in said linker such that the VH and VL domains from the scFv antibody can bind to the T cell.
2. The composition according to claim 1 , wherein the further moiety scFv antibody is an antibody specific for CD3.
3. A composition according to claim 1 , wherein the targeting moiety antibody or antigen-binding fragment thereof is
(i) specific for any of Her2/Neu; CD22; EpCAM; EGFR; PMSA; CD30; CD20; CD33; membrane IgE; IgE Receptor, CD80; CD86; CD2; CA125; Carbonic Anhydrase IX; CD70; CD74; CD56; CD40; CD19; c-met/HGFR; TRAIL-R1; DR5; PD-1; PD1L; IGF-1R; VEGF-R2; Prostate stem cell antigen; MUC1; CanAg; Mesothelin; P-cadherin; Myostatin; Cripto; ACVRL1/ALK1; MUC5AC; CEACAM; SLC44A4; CD2/CS1; CD137; CXCR4; Neuropilin 1; Glypican; HER3/EGFR; PDGFRa and EphA2, or
(ii) an anti-epidermal growth factor receptor antibody, an anti-Her2 antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD70 antibody, an anti-CD33 antibody, an anti-MUC1 antibody, an anti-CD40 antibody, an anti-CD74 antibody, an anti-P-cadherin antibody, an anti-EpCAM antibody, an anti-CD138 antibody, an anti-E-cadherin antibody, an anti-CEA antibody and an anti-FGFR3 antibody.
4. A composition according to claim 1 , wherein each of the further moiety and targeting moiety are parts of a single polypeptide chain.
5. A pharmaceutical composition, comprising a composition according to claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient.
6. A method of treating a tumour, the method comprising:
(i) administering a compositions according to claim 1 to a subject or
(ii) administering a composition according to claim 1 and a further therapeutic agent, which may include one or more of an immunostimulatory drug, an anti-cancer agent, and an inhibitor of an antibody response against the agent of the invention.
7. A composition according to claim 6 comprising
(i) composition according to claim 1 and
(ii) a further therapeutic agent suitable for treating a tumour,
for use in treating a tumour, optionally wherein the further therapeutic agent is one or more of an immunostimulatory drug, an anti-cancer agent, and an inhibitor of an antibody response against the agent of the invention.
8. The composition of claim 3 , wherein the targeting moiety antibody or antigen-binding fragment thereof is Cetuximab, Rituximab, Inotuzumab, or Gemtuzumab.
9. The method according to claim 7 , wherein the tumour is chosen from leukaemia, lymphoma, sarcoma, or carcinoma.
10. The composition according to claim 1 , wherein the targeting moiety antibody or antigen-binding fragment thereof is a full-length antibody.
11. The composition according to claim 1 , wherein the targeting moiety antibody or antigen-binding fragment thereof is an antigen binding fragment of an antibody.
12. The composition according to claim 1 , wherein the targeting moiety antibody or antigen-binding fragment thereof is a single chain antibody construct.
13. The composition according to claim 1 , wherein the targeting moiety antibody or antigen binding fragment thereof is an scFv, a camelid antibody, or an engineered camelid antibody.
14. The composition according to claim 1 , wherein the targeting moiety antibody or antigen binding fragment thereof is a human or humanized antibody or antigen binding fragment thereof.
15. The composition according to claim 1 , wherein the further moiety scFv antibody is a human scFv or a humanized scFv.
16. The composition according to claim 1 , wherein the linker in the further moiety that joins the heavy chain variable domain (VH) and light chain variable domain (VL) of insufficient length is a peptide linker of 14 or less amino acids.
17. The composition according to claim 16 , wherein the peptide linker is of 9 amino acids.
18. The composition according to claim 16 , wherein the peptide linker is of 8 amino acids.
19. The composition according to claim 16 , wherein the peptide linker is of 7 amino acids.
20. The composition according to claim 1 , wherein the further moiety scFv antibody is an antibody specific for TCR.