Constructs targeting histone H3 peptide/MHC complexes and uses thereof

1. An isolated anti-HMC construct comprising an antibody moiety that specifically binds to a complex comprising a histone H3 peptide and a major histocompatibility (MHC) class I protein (“HMC”); wherein:

the histone H3 peptide is the peptide set forth in SEQ ID NO: 7;

the MEW is HLA-A02; and

the antibody moiety comprises:

i) a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 99, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 108, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 117; and a light chain variable domain (VL) comprising a light chain complementarity determining region (LC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 129, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 139, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 148; or

ii) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 99, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 108, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 129, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 140, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 149; or

iii) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 99, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 108, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 119; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 130, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 140, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 148; or

iv) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 99, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 108, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 120; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 130, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 140, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 148; or

v) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 109, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 121; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 131, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 141, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 150; or

vi) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 110, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 122; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 132, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 142, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 151; or

vii) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 111, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 123; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 133, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 152; or

viii) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 103, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 134, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; or

ix) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 104, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 113, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 135, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 154; or

x) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 126; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 136, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 155; or

xi) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 106, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 115, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 127; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 137, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 156; or

xii) a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 107, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 128; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 138, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 147, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

2. The isolated anti-HMC construct of claim 1 wherein the antibody moiety comprises:

a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 75 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 75, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 87; or

b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 76 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 76, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 88; or

c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 77 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 77, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 89 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 89; or

d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 78 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 78, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 90; or

e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 79 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 79, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 91; or

f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 80 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 80, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 92 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 92; or

g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 81 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 81, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 93 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 93; or

h) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 82, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 94 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 94; or

i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 83 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 83, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 95 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 95; or

i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 84 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 84, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 96 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 96; or

k) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 85 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 85, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 97 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 97; or

l) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 86 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 86, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 98 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 98.

3. The isolated anti-HMC construct of claim 1 , wherein the isolated anti-HMC construct is multispecific.

4. The isolated anti-HMC construct of claim 3 , wherein the isolated anti-HMC construct is a tandem scFv comprising two scFvs linked by a peptide linker.

5. The isolated anti-HMC construct of claim 3 , wherein the isolated anti-HMC construct further comprises a second antibody moiety that specifically binds to a second antigen, wherein the second antigen is selected from the group consisting of CD3γ, CD3δ, CD3ε, CD3ζ, CD28, OX40, GITR, CD137, CD27, CD40L, and HVEM.

6. The isolated anti-HMC construct of claim 5 , wherein the second antigen is CD3ε, and wherein the isolated anti-HMC construct is a tandem scFv comprising a first scFv specific for the histone H3/MHC class I complex and a second scFv specific for CD3ε.

7. The isolated anti-HMC construct of claim 1 , wherein the isolated anti-HMC construct is a chimeric antigen receptor (CAR) comprising an extracellular domain comprising the antibody moiety, a transmembrane domain, and an intracellular signaling domain.

8. The isolated anti-HMC construct of claim 7 , wherein:

(i) the intracellular signaling domain comprises a CD3ζ intracellular signaling sequence and a CD28 intracellular signaling sequence; or

(ii) the intracellular signaling domain comprises a CD3ζ intracellular signaling sequence and a 4-1BB intracellular signaling sequence; or

(iii) the intracellular signaling domain comprises a CD3ζ intracellular signaling sequence, a CD28 intracellular signaling sequence and a 4-1BB intracellular signaling sequence.

9. An effector cell expressing the anti-HMC construct of claim 7 .

10. The effector cell of claim 9 , wherein the effector cell is a T cell.

11. A pharmaceutical composition comprising the effector cell of claim 10 and a pharmaceutically acceptable carrier.

12. The isolated anti-HMC construct of claim 1 , wherein the isolated anti-HMC construct is a chimeric antibody/T cell receptor (abTCR) comprising an extracellular domain comprising the antibody moiety and a T cell receptor (TCR) module (TCRM) comprising TCR transmembrane domains.

13. The isolated anti-HMC construct of claim 12 , wherein the antibody moiety comprises:

a) a first polypeptide chain comprising a first antigen-binding domain comprising V H and C H 1 antibody domains; and

b) a second polypeptide chain comprising a second antigen-binding domain comprising V L and C L antibody domains,

wherein the V H and C H 1 domains of the first antigen-binding domain and the V L and C L domains of the second antigen-binding domain form a Fab-like antigen-binding module that specifically binds to the HMC.

14. An effector cell expressing the anti-HMC construct of claim 12 .

15. The effector cell of claim 14 , wherein the effector cell is a T cell.

16. A pharmaceutical composition comprising the effector cell of claim 15 and a pharmaceutically acceptable carrier.

17. The isolated anti-HMC construct of claim 1 , wherein the isolated anti-HMC construct is an immunoconjugate comprising the antibody moiety and an effector molecule, wherein the effector molecule is a therapeutic agent selected from the group consisting of a drug, a toxin, a radioisotope, a protein, a peptide, and a nucleic acid.

18. A pharmaceutical composition comprising the immunoconjugate of claim 17 and a pharmaceutically acceptable carrier.

19. The isolated anti-HMC construct of claim 1 , wherein the isolated anti-HMC construct is an immunoconjugate comprising the antibody moiety and a label.

20. The isolated anti-HMC construct of claim 1 , wherein the antibody moiety comprises a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 103, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 134, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 153.

21. The isolated anti-HMC construct of claim 1 , wherein the antibody moiety comprises a VH comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 106, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 115, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 127; and a VL comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 137, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 156.

22. A pharmaceutical composition comprising the anti-HMC construct of claim 1 and a pharmaceutically acceptable carrier.

23. A host cell expressing the anti-HMC construct of claim 1 .

24. A nucleic acid encoding the anti-HMC construct of claim 1 .

25. An isolated antibody construct comprising an antibody moiety that specifically binds to a complex comprising the histone H3 peptide set forth in SEQ ID NO: 7 and HLA-A02; wherein the antibody moiety comprises

a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 75 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 87; or

b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 76 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 88; or

c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 77 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 89; or

d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 78 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 90; or

e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 79 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 91; or

f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 80 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 92; or

g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 81 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 93; or

h) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 94; or

i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 83 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 95; or

j) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 96; or

k) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 85 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 97; or

l) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 98.

26. The isolated anti-HMC construct of claim 25 , wherein the antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 94.

27. The isolated anti-HMC construct of claim 25 , wherein the antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 85 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 97.

28. A nucleic acid encoding the antibody moiety of claim 25 .