IP Library › Granted Patent US 12,673,993
Granted Patent B2
US 12,673,993 · App. 16/021,777 · Granted Jul 7, 2026

Functional antibody fragment complementation for a two-components system for redirected killing of unwanted cells

Inventor: Mark Cobbold (Winchester, MA)
Assignee: Revitope Limited
C07K16/2809C07K16/18C07K16/2863C07K16/2896C07K16/30C07K16/303A61K38/00A61K39/39558A61K2039/505C07K2317/31C07K2317/569C07K2317/622C07K2317/94
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Quick Facts
Patent No.
US 12,673,993
App. No.
16/021,777
Filed
Jun 28, 2018
Granted
Jul 7, 2026
Kind
B2
Art Unit
1646
USPC
424/135.1
Abstract

A targeted T-cell engaging agent for treating a condition characterized by the presence of unwanted cells includes (a) a targeting moiety that is capable of targeting the unwanted cells; (b) a first T-cell engaging domain capable of T-cell engaging activity when binding a second T-cell engaging domain, wherein the second T-cell engaging domain is not part of the agent; (c) at least one inert binding partner capable of binding to the first T-cell engaging domain such that the first T-cell engaging domain does not bind to the second T-cell engaging domain unless the inert binding partner is removed; and (d) at least one cleavage site separating the first T-cell engaging domain and the inert binding partner, wherein the cleavage site is: (i) cleaved by an enzyme expressed by the unwanted cells; (ii) cleaved through a pH-sensitive cleavage reaction inside the unwanted cell; (iii) cleaved by a complement-dependent cleavage reaction; or (iv) cleaved by a protease that is colocalized to the unwanted cell by a targeting moiety that is the same or different from the targeting moiety in the agent.

Claims (109)

1 . A kit or composition for treating cancer in a human patient comprising two single-molecule components:

a) a first single-molecule component comprising a targeted T-cell binding agent comprising:

i. a first targeting moiety that binds a human tumor antigen expressed by the cancer, wherein the first targeting moiety that binds a human tumor antigen expressed by the cancer is an antibody or antigen binding fragment thereof; linked to

ii. a first T-cell binding domain capable of T-cell binding activity to a human T-cell in the patient when binding a second T-cell binding domain capable of T-cell binding activity to a human T-cell in the patient, wherein the second T-cell binding domain is not part of the first single-molecule component, and wherein the first T-cell binding domain is a VH domain; linked to

iii. a first peptide linker comprising a protease cleavage site; linked to

iv. a first inert binding partner for the first T-cell binding domain, wherein the first inert binding partner binds to the first T-cell binding domain such that the first T-cell binding domain does not bind to the second T-cell binding domain unless the first inert binding partner is removed, wherein the first inert binding partner is a VL domain;

wherein the protease cleavage site is capable of releasing the inert binding partner from the T-cell binding domain in the presence of a protease expressed by the cancer;

b) a second single-molecule component comprising:

i. a second targeting moiety that binds a human tumor antigen expressed by the cancer, wherein the second targeting moiety that binds a human tumor antigen expressed by the cancer is an antibody or antigen binding fragment thereof; linked to

ii. the second T-cell binding domain capable of T-cell binding activity to a human T-cell in the patient when binding the first T-cell binding domain, wherein the first and second T-cell binding domains are capable of binding CD3 or a T cell receptor (TCR) when neither is bound to an inert binding partner, and wherein the second T-cell binding domain is a VL domain; linked to

iii. a second peptide linker comprising a protease cleavage site; linked to

iv. a second inert binding partner for the second T-cell binding domain, wherein the second inert binding partner binds to the second T-cell binding domain such that the second T-cell binding domain does not bind to the first T-cell binding domain unless the second inert binding partner is removed, wherein the second inert binding partner is a VH domain;

wherein the protease cleavage site is capable of releasing the second inert binding partner from the T-cell binding domain in the presence of a protease expressed by the cancer;

wherein the first and second single-molecule components are capable of being administered to the patient.

2 . The kit or composition of claim 1 , wherein the first and second targeting moieties target different tumor antigens.

3 . The kit or composition of claim 1 , wherein the first and second targeting moieties are different.

4 . The kit or composition of claim 1 , wherein the protease cleavage sites of the first single-molecule component and second single-molecule component are different.

5 . The kit or composition of claim 1 , wherein the antibody or antigen binding fragment thereof binds Her2/Neu; CD22; PSMA; CD30; CD20; CD33; CD80; CD86; CD2; CA125; Carbonic Anhydrase IX; CD70; CD74; CD56; CD40; CD19; c-met/HGFR; TRAIL-R1; DRS; PD-1; IGF-1R; VEGF-R2; PSCA; MUC1; CanAg; Mesothelin; P-cadherin; Myostatin; Cripto; ACVRL 1/ALK1; MUC5AC; CEACAM; CD137; CXCR4; Neuropilin 1; Glypicans; HER3/EGFR; PDGFRa; EphA2; CD38; CD138/Syndecan1; α4-integrin; EpCAM, PD-L1, FGFR3, DR5, CD4, or CEA.

6 . The kit or composition of claim 1 , wherein the antibody or antigen binding fragment thereof is 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, an anti-FGFR3 antibody, an anti a4-integrin antibody, an anti-CD80 antibody, an anti-mucin core protein antibody, an anti-transferrin antibody, an anti-gp95/97 antibody, an anti-p-glycoprotein antibody, an anti-TRAIL-R1 antibody, an anti-DR5 antibody, an anti-IL-4 antibody, an anti-IL-6 antibody, an anti-CD19 antibody, an anti-PSMA antibody, an anti-PSCA antibody, an anti-Cripto antibody, an anti-PD-L1 antibody, an anti-IGF-IR antibody, an anti-CD38 antibody, an anti-CD123 antibody, antibody, or an antigen binding fragment thereof.

7 . The kit or composition of claim 1 , wherein the antibody or antigen binding fragment thereof is Cetuximab, Rituximab, Inotuzumab, Gemtuzumab, Natalizumab, or an antigen binding fragment thereof.

8 . The kit or composition of claim 1 , wherein the first and second targeting moieties are each an antibody or antigen binding fragment thereof, and

a. the first single-molecule component comprises, from N-terminus to C-terminus:

i. the first targeting moiety;

ii. the first T-cell binding domain;

iii. the first peptide linker; and

iv. the first inert binding partner; and

b. the second single-molecule component comprises, from N-terminus to C-terminus:

i. the second targeting moiety;

ii. the second T-cell binding domain;

iii. the second peptide linker; and

iv. the second inert binding partner.

9 . The kit or composition of claim 1 , wherein the first and second targeting moieties are each an antibody or antigen binding fragment thereof; and

a. the first single-molecule component comprises, from N-terminus to C-terminus:

i. the first inert binding partner;

ii. the first peptide linker; and

iii. the first T-cell binding domain; and

iv. the first targeting moiety; and

b. the second single-molecule component comprises, from N-terminus to C-terminus:

i. the second inert binding partner;

ii. the second peptide linker;

iii. the second T-cell binding domain; and

iv. the second targeting moiety.

10 . The kit or composition of claim 1 , wherein:

a. if the first targeting moiety is an antibody or antigen binding fragment thereof, the first single-molecule component comprises a peptide linker between the first targeting moiety and the first T-cell binding domain; and/or

b. if the second targeting moiety is an antibody or antigen binding fragment thereof, the second single-molecule component comprises a peptide linker between the second targeting moiety and the second T-cell binding domain.

11 . The kit or composition of claim 1 , wherein the first and/or second targeting moiety is an antibody or antigen binding fragment thereof selected from an scFv, Fv, VHH, Fab, immunoglobulin devoid of light chains, Fab′, F (ab′)2, diabody, scAB, single-domain heavy chain antibody, single-domain light chain antibody, or Fd.

12 . The kit or composition of claim 1 , wherein the antibody or antigen binding fragment thereof:

a. binds ADAM17, CD59, Integrin aV, Integrin aVB3, MCP-1, PCLA, RANKL, RG1, SLC44A4, STEAP-1, VEGF-C, CCN1, CD44, CD98, c-RET, DLL4, Episialin, GPNMB, Integrin α6β4, LFL2, LIV-1, Ly6E, MUC18, NRP1, Phosphatidylserine, PRLR, TACSTD-2, Tenascin C, TWEAKR, VANGL2, PD-L1, PD-L2, BCMA, DKK-1, ICAM-1, GRP78, SLAMF6, CD48, CD71, APRIL, DR5, CD37, HLA-DR, CD70b, CAIX, TPBG, ENPP3, FGFR1, VEGFR-2, CLDN18, GCC, C242, FGFR2, GPR49, IGFR, ALK, GD2, EGFRVIII, CD5, IL-3Ra, Integrin α5β1, Lewis y/b antigen, EGFL7, NaPi2b, flt4, CD133, CD123, CD45, c-Kit, Lewis Y, Siglec-15, FLT-3, CEACAMI, Cadherin-19, GM3, TYRP1, GD3, MUC5A, CLDN6, Glypican-3, FGFR4, PIVKA-II, PLVAP, Progastrin, CLDN1, A33, CK8, or FAP; and/or

b. is an anti-CD49d antibody, an anti-glypican 3 antibody, or an anti-IL-13R antibody.

13 . A kit or composition for treating cancer in a human patient comprising two single-molecule components:

a) a first single-molecule component comprising a targeted T-cell binding agent comprising:

i. a first targeting moiety that binds a human tumor antigen expressed by the cancer, wherein the first targeting moiety that binds a human tumor antigen expressed by the cancer is an element chosen from an antibody or antigen binding fragment thereof, an aptamer, human IL-2, human IL-4, human IL-6, human α-MSH, human transferrin, folic acid, human EGF, human TGFα, human PD1, human IL-13, human stem cell factor, human insulin-like growth factor (IGF), and human CD40; linked to

ii. a first T-cell binding domain capable of T-cell binding activity to a human T-cell in the patient when binding a second T-cell binding domain capable of T-cell binding activity to a human T-cell in the patient, wherein the second T-cell binding domain is not part of the first single-molecule component, and wherein the first T-cell binding domain is a VH domain; linked to

iii. a first peptide linker comprising a protease cleavage site; linked to

iv. a first inert binding partner for the first T-cell binding domain, wherein the first inert binding partner binds to the first T-cell binding domain such that the first T-cell binding domain does not bind to the second T-cell binding domain unless the first inert binding partner is removed, wherein the first inert binding partner is a VL domain;

wherein the protease cleavage site is capable of releasing the inert binding partner from the T-cell binding domain in the presence of a protease expressed by the cancer;

b) a second single-molecule component comprising:

i. a second targeting moiety that binds a human tumor antigen expressed by the cancer, wherein the second targeting moiety that binds a human tumor antigen expressed by the cancer is an element chosen from an antibody or antigen binding fragment thereof, an aptamer, human IL-2, human IL-4, human IL-6, human α-MSH, human transferrin, folic acid, human EGF, human TGFα, human PD1, human IL-13, human stem cell factor, human insulin-like growth factor (IGF), and human CD40; linked to

ii. the second T-cell binding domain capable of T-cell binding activity to a human T-cell in the patient when binding the first T-cell binding domain, wherein the first and second T-cell binding domains are capable of binding CD3 or a T cell receptor (TCR) when neither is bound to an inert binding partner, and wherein the second T-cell binding domain is a VL domain; linked to

iii. a second peptide linker comprising a protease cleavage site; linked to

iv. a second inert binding partner for the second T-cell binding domain, wherein the second inert binding partner binds to the second T-cell binding domain such that the second T-cell binding domain does not bind to the first T-cell binding domain unless the second inert binding partner is removed, wherein the second inert binding partner is a VH domain;

wherein the protease cleavage site is capable of releasing the second inert binding partner from the T-cell binding domain in the presence of a protease expressed by the cancer;

wherein the first and second single-molecule components are capable of being administered to the patient.

14 . The kit or composition of claim 13 , wherein the first and second targeting moieties are each independently an element chosen from an antibody or antigen binding fragment thereof, human IL-2, human IL-4, human IL-6, human α-MSH, human transferrin, human EGF, human TGFα, human PD1, human IL-13, human stem cell factor, human insulin-like growth factor (IGF), and human CD40; and

a. the first single-molecule component comprises, from N-terminus to C-terminus:

i. the first targeting moiety;

ii. the first T-cell binding domain;

iii. the first peptide linker; and

iv. the first inert binding partner; and

b. the second single-molecule component comprises, from N-terminus to C-terminus:

i. the second targeting moiety;

ii. the second T-cell binding domain;

iii. the second peptide linker; and

iv. the second inert binding partner.

15 . The kit or composition of claim 13 , wherein the first and second targeting moieties are each independently an element chosen from an antibody or antigen binding fragment thereof, human IL-2, human IL-4, human IL-6, human α-MSH, human transferrin, human EGF, human TGFα, human PD1, human IL-13, human stem cell factor, human insulin-like growth factor (IGF), and human CD40; and

a. the first single-molecule component comprises, from N-terminus to C-terminus:

i. the first inert binding partner;

ii. the first peptide linker; and

iii. the first T-cell binding domain; and

iv. the first targeting moiety; and

b. the second single-molecule component comprises, from N-terminus to C-terminus:

i. the second inert binding partner;

ii. the second peptide linker;

iii. the second T-cell binding domain; and

iv. the second targeting moiety.

16 . The kit or composition of claim 13 , wherein:

a. if the first targeting moiety is an antibody or antigen binding fragment thereof, human IL-2, human IL-4, human IL-6, human α-MSH, human transferrin, folic acid, human EGF, human TGFα, human PD1, human IL-13, human stem cell factor, human insulin-like growth factor (IGF), or human CD40, the first single-molecule component comprises a peptide linker between the first targeting moiety and the first T-cell binding domain; and/or

b. if the second targeting moiety is an antibody or antigen binding fragment thereof, human IL-2, human IL-4, human IL-6, human α-MSH, human transferrin, folic acid, human EGF, human TGFα, human PD1, human IL-13, human stem cell factor, human insulin-like growth factor (IGF), or human CD40, the second single-molecule component comprises a peptide linker between the second targeting moiety and the second T-cell binding domain.

17 . The kit or composition of claim 13 , wherein the first and/or second targeting moiety is an aptamer that binds to the tumor antigen.

18 . The kit or composition of claim 17 , wherein the aptamer comprises DNA.

19 . The kit or composition of claim 17 , wherein the aptamer is a cancer cell-specific aptamer selected from a random candidate library.

20 . The kit or composition of claim 17 , wherein the tumor antigen expressed by the cancer is EGFR and the first targeting moiety comprises an aptamer and further wherein the aptamer is an anti-EGFR aptamer.

21 . The kit or composition of claim 20 , wherein the anti-EGFR aptamer comprises any one of SEQ ID NOs: 95-164.

22 . The kit or composition of claim 17 , wherein the aptamer binds to the tumor antigen expressed by the cancer with a Kd from 1 picomolar to 500 nanomolar.

23 . The kit or composition of claim 22 , wherein the aptamer binds to the tumor antigen expressed by the cancer with a Kd from 1 picomolar to 100 nanomolar.

24 . The kit or composition of claim 13 , wherein the first and/or second targeting moiety is human IL-2, human IL-4, human IL-6, human α-MSH, human transferrin, folic acid, human EGF, human TGFα, human PD1, human IL-13, human stem cell factor, human insulin-like growth factor (IGF), or human CD40.

25 . The kit or composition of claim 24 , wherein:

a. if at least one of the tumor antigens expressed by the cancer is the IL-2 receptor, the first and/or second targeting moiety is human IL-2;

b. if at least one of the tumor antigens expressed by the cancer is the IL-4 receptor, the first and/or second targeting moiety is human IL-4;

c. if at least one of the tumor antigens expressed by the cancer is the IL-6 receptor, the first and/or second targeting moiety is human IL-6;

d. if at least one of the tumor antigens expressed by the cancer is the melanocyte stimulating hormone receptor (MSH receptor), the first and/or second targeting moiety is human α-MSH;

e. if at least one of the tumor antigens expressed by the cancer is the transferrin receptor (TR), the first and/or second targeting moiety is human transferrin;

f. if at least one of the tumor antigens expressed by the cancer is folate receptor 1 (FOLR) or FOLH1 (folate hydroxylase), the first and/or second targeting moiety is folic acid;

g. if at least one of the tumor antigens expressed by the cancer is EGF receptor (EGFR), the first and/or second targeting moiety is human epidermal growth factor (EGF) or TGFα;

h. if at least one of the tumor antigens expressed by the cancer is PD-L1 or PD-L2, the first and/or second targeting moiety is human PD-1;

i. if at least one of the tumor antigens expressed by the cancer is IL-13R, the first and/or second targeting moiety is human IL-13;

j. if at least one of the tumor antigens expressed by the cancer is CXCR4, the first and/or second targeting moiety is human stem cell factor;

k. if at least one of the tumor antigens expressed by the cancer is IGFR, the first and/or second targeting moiety is human insulin-like growth factor (IGF); or

l. if at least one of the tumor antigens expressed by the cancer is CD40L, the first and/or second targeting moiety is human CD40.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 31, 2018
From: COBBOLD, MARK
To: REVITOPE LIMITED
Reel/Frame 046978/0237 →
Continuity (4)
Continuation 15355511 · Nov 18, 2016
Provisional Application 62270907 · Dec 22, 2015
Provisional Application 62257552 · Nov 19, 2015
Related Publication 20180346568A1 · Dec 6, 2018
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