Granted Patent B2

US 12,312,408 · App. 18/451,047 · Granted May 27, 2025

Inventors: Mihriban Tuna (Cambridge, GB); Mark Uden (London, GB); Joshua Freedman (London, GB); Natalie Mount (London, GB)

Assignees: GammaDelta Therapeutics Ltd; F-star Therapeutics Limited

C07K16/2863C07K16/2809C07K2317/31

Abstract

Claims (39)

1. A multispecific antibody comprising:

a variable delta 1 (Vδ1) chain of a γδ T cell receptor (TCR) binding site, comprising:

(i) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 133, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80 and 83, respectively;

(ii) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53, and 68, respectively; and a VLCDR1, VLCDR2, and a VLCDR3 of SEQ ID NO: 79, 80 and 95, respectively; or

(iii) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 136, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80 and 86, respectively;

and

a fragment crystallizable (Fc) region that comprises an epidermal growth factor receptor (EGFR) binding site in the CH3 domain of the Fc region in which, according to EU antibody numbering:

a. residues 359 to 362 comprise EEGP (SEQ ID NO: 523), residues 384 to 386 comprise TYG (SEQ ID NO:511), and residues 413 to 419 comprise SYWRWYK (SEQ ID NO: 512);

b. residues 359 to 362 comprise EEGP (SEQ ID NO: 523), and residues 413 to 419 comprise SYWRWYK (SEQ ID NO: 512);

c. residues 359 to 362 comprise EEGP (SEQ ID NO: 523) and residues 413 to 415 comprise SYW (SEQ ID NO: 533);

d. residues 359 to 362 comprise EEGP (SEQ ID NO: 523), residues 384 to 386 comprise TYG (SEQ ID NO: 511), and residues 413 to 415 comprise SYW (SEQ ID NO: 533);

e. residues 358 to 361, 361.1 and 362 comprise LDEGGP (SEQ ID NO: 542), residues 384 to 386 comprise TYG (SEQ ID NO: 511), and residues 413 to 419 comprise SYWRWVK (SEQ ID NO: 543);

f. residues 384 to 386 comprise TYG (SEQ ID NO: 511), and residues 413 to 419 comprise SYWRWYK (SEQ ID NO: 512);

g. residues 358 to 362 comprise TDDGP (SEQ ID NO: 560), residues 384 to 386 comprise TYG (SEQ ID NO: 511), and residues 413 to 419 comprise SYWRWYK (SEQ ID NO: 512); or

h. residues 358 to 362 comprise TESGP (SEQ ID NO: 553), residues 384 to 386 comprise KFG (SEQ ID NO: 554), residues 413 to 421 comprise SNLRWTKGH (SEQ ID NO: 555), and residue 378 is valine.

2. The multispecific antibody of claim 1 , wherein the EGFR binding site is in the CH3 domain in which, according to EU antibody numbering:

a. residues 355 to 362 form an AB loop comprising RDELEEGP (SEQ ID NO: 524) and residues 413 to 422 form an EF loop comprising SYWRWYKGNV (SEQ ID NO: 515);

b. residues 355 to 362 form an AB loop comprising RDELEEGP (SEQ ID NO: 524), residues 383 to 391 form a CD loop comprising STYGPENNY (SEQ ID NO: 514) and residues 413 to 422 form an EF loop comprising SYWRWYKGNV (SEQ ID NO: 515);

c. residues 355 to 362 form an AB loop comprising RDELEEGP (SEQ ID NO: 524), residues 383 to 391 form a CD loop comprising SNGQPENNY (SEQ ID NO: 525) and residues 413 to 422 form an EF loop comprising SYWRWYKGNV (SEQ ID NO: 515);

d. residues 355 to 362 form an AB loop comprising RDELEEGP (SEQ ID NO: 524) residues 413 to 422 form an EF loop comprising SYWRWQQGNV (SEQ ID NO: 534);

e. residues 355 to 362 form an AB loop comprising RDELEEGP (SEQ ID NO: 524), residues 383 to 391 form a CD loop comprising STYGPENNY (SEQ ID NO: 514) and residues 413 to 422 form an EF loop comprising SYWRWQQGNV (SEQ ID NO: 534);

f. residues 355 to 362 form an AB loop comprising RDELDEGGP (SEQ ID NO: 544), residues 383 to 391 form a CD loop comprising STYGPENNY (SEQ ID NO: 514), and residues 413 to 422 form an EF loop comprising SYWRWVKGNV (SEQ ID NO: 545);

g. residues 355 to 362 form an AB loop comprising RDELTKNQ (SEQ ID NO: 513), residues 383 to 391 form a CD loop comprising STYGPENNY (SEQ ID NO: 514) and residues 413 to 422 form an EF loop comprising SYWRWYKGNV (SEQ ID NO: 515);

h. residues 355 to 362 form an AB loop comprising RDETDDGP (SEQ ID NO: 561), residues 383 to 391 according to form a CD loop comprising STYGPENNY (SEQ ID NO: 514), residues 413 to 422 form an EF loop comprising SYWRWYKGNV (SEQ ID NO: 515); or

i. residues 355 to 362 form an AB loop comprising RDETESGP (SEQ ID NO: 556), residues 383 to 391 form a CD loop comprising SKFGPENNY (SEQ ID NO: 557), residues 413 to 422 form an EF loop comprising SNLRWTKGHV (SEQ ID NO: 558) and residue 378 is valine.

3. The multispecific antibody of claim 1 , wherein the EGFR binding site CH3 domain does not comprise a CH3 domain in which, according to EU antibody numbering:

a. residues 358 to 362 comprise TDDGP (SEQ ID NO: 560), residues 384 to 386 comprise TYG (SEQ ID NO: 511), and residues 413 to 419 comprise SYWRWYK (SEQ ID NO: 512); or

b. residues 355 to 362 form an AB loop comprising RDETDDGP (SEQ ID NO: 561), residues 383 to 391 form a CD loop comprising STYGPENNY (SEQ ID NO: 514), residues 413 to 422 form an EF loop comprising SYWRWYKGNV (SEQ ID NO: 515).

4. The multispecific antibody of claim 1 , wherein the CH3 domain is a human IgG CH3 domain.

5. The multispecific antibody of claim 4 , wherein the Fc region is a human IgG Fc region.

6. The multispecific antibody of claim 1 , wherein the antibody is Fc enabled.

7. The multispecific antibody of claim 1 , wherein the Vδ1 TCR binding site is in a Fab region of the multispecific antibody.

8. The multispecific antibody of claim 7 , wherein the Fab region comprises an amino acid residue other than serine at position 74, according to the IMGT numbering system.

9. A pharmaceutical composition comprising the multispecific antibody of claim 1 and a pharmaceutically acceptable diluent or carrier.

10. A method of treating an EGFR expressing cancer in a subject, comprising administering to the subject the multispecific antibody of claim 1 .

11. The multispecific antibody of claim 7 , wherein the Vδ1 TCR binding site comprises the VHCDR1, the VHCDR2 and the VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 133, respectively, and the VLCDR1, the VLCDR2 and the VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80 and 83, respectively.

12. The multispecific antibody of claim 1 , wherein the Vδ1 TCR binding site comprises the VHCDR1, the VHCDR2 and the VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 136, respectively, and the VLCDR1, the VLCDR2 and the VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80 and 86, respectively.

13. The multispecific antibody of claim 1 , wherein the Vδ1 TCR binding site comprises the VHCDR1, the VHCDR2 and the VHCDR3 comprises the amino acid sequences of SEQ ID NO: 51, 53 and 68, respectively, and the VLCDR1, the VLCDR2 and the VLCDR3 comprises the amino acid sequences of SEQ ID NOs: 79, 80 and 95, respectively.

14. The multispecific antibody of claim 8 , wherein the residue at position 74 according to the IMGT numbering system is a leucine residue.

Assignments (3)

Priority Claims (2)

Continuity (2)

References Cited (105)

Cited By (2)

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