IP Library › Granted Patent US 12,296,012
Granted Patent B2
US 12,296,012 · App. 16/617,487 · Granted May 13, 2025

Chimeric antigen receptors targeting FLT3

Inventors: Barbra Johnson Sasu (San Francisco, CA); Danielle Elizabeth Dettling (San Francisco, CA); Cesar Adolfo Sommer (San Mateo, CA); Yik Andy Yeung (South San Francisco, CA); Moustafa Marc Hamze (Nogent-sur-Marne, FR)
Assignee: PFIZER INC.
A61K45/06A61K39/3955A61K39/4611A61K39/4631A61K39/464462A61P35/02C07K14/7051C07K14/70517C07K14/7151C07K16/2863A61K38/00A61K2239/31A61K2239/38A61K2239/48C07K2317/622C07K2317/92
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Quick Facts
Patent No.
US 12,296,012
App. No.
16/617,487
Granted
May 13, 2025
Kind
B2
Abstract

Provided herein are antibodies that specifically bind to Fms-like tyrosine kinase 3 (FLT3), chimeric antigen receptors (CARs) that specifically bind to FLT3, and engineered immune cells expressing such CARs (e.g. FLT3-specific CAR-T cells). The invention also provides making such antibodies, CARs, and engineered immune cells. The invention also provides using such antibodies, CARs, and engineered immune cells, for example for the treatment of a condition associated with malignant cells expressing FLT3 (e.g., cancer).

Claims (55)

1. A Fms-like tyrosine kinase 3 (FLT3) specific chimeric antigen receptor (CAR) comprising an extracellular ligand-binding domain, a first transmembrane domain, and an intracellular signaling domain, wherein the extracellular ligand-binding domain comprises a single chain variable fragment (scFv) comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:

(a) the VH region comprises (i) a VH complementarity determining region one (CDR1) having the amino acid sequence shown in SEQ ID NO: 90, 91, or 92, (ii) a VH complementarity determining region two (CDR2) having the amino acid sequence shown in SEQ ID NO: 93 or 94, and (iii) a VH complementarity determining region three (CDR3) having the amino acid sequence shown in SEQ ID NO: 95; and

the VL region comprises (i) a VL complementarity determining region one (CDR1) having the amino acid sequence shown in SEQ ID NO: 171; (ii) a VL complementarity determining region two (CDR2) having the amino acid sequence shown in SEQ ID NO: 172; and (iii) a VL complementarity determining region three (CDR3) having the amino acid sequence shown in SEQ ID NO: 173;

(b) the VH region comprises a VH CDR1 comprising the amino acid sequence shown in SEQ ID NO: 49, 44, or 50; a VH CDR2 comprising the amino acid sequence shown in SEQ ID NO: 51 or 52; and a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 53; and the VL region comprises a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO: 150; a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 151; and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 152;

(c) the VH region comprises a VH CDR1 comprising the amino acid sequence shown in SEQ ID NO: 60, 61, or 62; a VH CDR2 comprising the amino acid sequence shown in SEQ ID NO: 63 or 64; and a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 65; and the VL region comprises a VL CDRI comprising the amino acid sequence shown in SEQ ID NO: 156; a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 157; and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 158;

(d) the VH region comprises a VH CDR1 comprising the amino acid sequence shown in SEQ ID NO: 84, 85, or 86; a VH CDR2 comprising the amino acid sequence shown in SEQ ID NO: 87 or 88; and a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 89; and the VL region comprises a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO: 168; a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 169; and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 170; or

(e) the VH region comprises a VH CDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, 109, or 110; a VH CDR2 comprising the amino acid sequence shown in SEQ ID NO: 111 or 112; and a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 113; and the VL region comprises a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO: 180; a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 181; and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 182.

2. The Fms-like tyrosine kinase 3 (FLT3) specific chimeric antigen receptor (CAR) of claim 1 , comprising an extracellular ligand-binding domain, a first transmembrane domain, and an intracellular signaling domain, wherein the extracellular ligand-binding domain comprises a single chain variable fragment (scFv) comprising a heavy chain variable (VH) region having the sequence shown in SEQ ID NO: 20, and a light chain variable (VL) region having the sequence shown in SEQ ID NO: 19.

3. The Fms-like tyrosine kinase 3 (FLT3) specific chimeric antigen receptor (CAR) of claim 1 , wherein

the VH region comprises a VH CDR1 comprising the amino acid sequence shown in SEQ ID NO: 90, 91, or 92; a VH CDR2 comprising the amino acid sequence shown in SEQ ID NO: 93 or 94; and a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 95; and the VL region comprises a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO: 171; a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 172; and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 173.

4. The FLT3 specific CAR of claim 1 , wherein:

the VH region comprises a VH CDR1 comprising the amino acid sequence shown in SEQ ID NO: 49, 44, or 50; a VH CDR2 comprising the amino acid sequence shown in SEQ ID NO: 51 or 52; and a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 53; and the VL region comprises a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO: 150; a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 151; and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 152.

5. The FLT3 specific CAR of claim 1 , wherein the CAR is characterized by one or more of the following:

(i) the intracellular signaling domain comprises a CD3ζ signaling domain or a 4-1BB domain;

(ii) the first transmembrane domain comprises a CD8a chain transmembrane domain;

(iii) the FLT3 specific CAR comprises a second intracellular signaling domain;

(iv) the FLT3 specific CAR comprises a stalk domain between the extracellular ligand-binding domain and the first transmembrane domain; and

(v) the FLT3 specific CAR comprises a second extracellular ligand-binding domain that is not specific for FLT3.

6. The FLT3 specific CAR of claim 1 , comprising one or more epitopes specific for a monoclonal antibody (iii).

7. The FLT3 specific CAR of claim 1 , wherein the FLT3 specific CAR comprises the amino acid sequence shown in SEQ ID NO: 235, 236, 237, 238, 240, or 242.

8. The FLT3 specific CAR of claim 1 , wherein: (i) the extracellular ligand-binding domain(s), the first transmembrane domain, and intracellular signaling domain(s) are on a single polypeptide; and/or (ii) the FLT3 specific CAR comprises a second transmembrane domain, wherein the first transmembrane domain and the extracellular ligand-binding domain(s) are on a first polypeptide, and wherein the second transmembrane domain and the intracellular signaling domain(s) are on a second polypeptide, wherein the first transmembrane domain comprises a transmembrane domain from the α chain of the high-affinity IgE receptor (FcεRI) and the second transmembrane domain comprises a transmembrane domain from the γ or β chain of FcεRI.

9. A polynucleotide comprising a nucleic acid sequence encoding a FLT3 specific CAR, wherein the polynucleotide comprises the nucleic acid sequence shown in SEQ ID NO: 249, 250, 253, 248, 247, 246, or 245, or comprises a nucleic acid sequence encoding a FLT3 specific CAR according to claim 1 .

10. An engineered immune cell expressing a FLT3 specific CAR of claim 1 .

11. The engineered immune cell of claim 10 , comprising any of (i) another CAR which is not specific for FLT3, (ii) a polynucleotide encoding a suicide polypeptide; and (iii) a disruption of one or more endogenous genes, wherein the endogenous gene encodes TCRa, TCRβ, CD52, glucocorticoid receptor (GR), deoxycytidine kinase (dCK), or an immune checkpoint protein; wherein the engineered immune cell is (iv) derived from an inflammatory T-lymphocyte, a cytotoxic T-lymphocyte, a regulatory T-lymphocyte, or a helper T-lymphocyte; or (v) is obtained from a healthy donor or from a donor suffering from a disease or disorder, or (iv) and (v).

12. The engineered immune cell of claim 10 , wherein the FLT3 specific CAR comprises an extracellular domain comprising an ScFv,

wherein the scFv binds to the extracellular domain of human FLT3 with a K D comprised between 10 nM and 80 nM, or

wherein the scFv binds to domain 4 of the extracellular domain of human FLT3 with a K D comprised between 1 nM and 100 nM, or

wherein the scFv binds to domain 2-3 of the extracellular domain of human FLT3 with a K D comprised between 5 nM and 30 nM.

13. A method of engineering an immune cell expressing a FLT3 specific CAR, comprising:

a. providing an immune cell; and

b. introducing into the cell at least one polynucleotide encoding a FLT3 specific CAR of claim 1

whereby the immune cell expresses the FLT3 specific CAR.

14. The FLT3 specific CAR of claim 1 , wherein:

(i) the intracellular signaling domain comprises a CD3ζ signaling domain which has an amino acid sequence comprising at least 90% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 210, and

(ii) the intracellular signaling domain further comprises one or more of a 4-1BB domain which has an amino acid sequence comprising at least 90% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 209 and a CD28 co-stimulatory domain which has an amino acid sequence comprising at least 90% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 214.

15. The FLT3 specific CAR of claim 14 , wherein

(iii) the first transmembrane domain comprises a CD8α chain transmembrane domain which has an amino acid sequence comprising at least 90% or 100% sequence identity with the amino acid sequence of SEQ ID NO:208; and/or

(iv) the FLT3 specific CAR comprises a stalk domain between the extracellular ligand-binding domain and the first transmembrane domain, wherein the stalk domain is selected from the group consisting of: a CD8α hinge which has an amino acid sequence comprising at least 90% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 206, an IgG1 hinge which has an amino acid sequence comprising at least 90% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 207, and an FcγRIIIα hinge which has an amino acid sequence comprising at least 90% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 205.

16. The FLT3 specific CAR of claim 1 , wherein:

(a) the VH region comprises the amino acid sequence shown in SEQ ID NO: 10 and the VL region comprises the amino acid sequence shown in SEQ ID NO: 9;

(b) the VH region comprises the amino acid sequence shown in SEQ ID NO: 18 and the VL region comprises the amino acid sequence shown in SEQ ID NO: 17; or

(c) the VH region comprises the amino acid sequence shown in SEQ ID NO: 26 and the VL region comprises the amino acid sequence shown in SEQ ID NO: 25.

17. The FLT3 specific CAR of claim 4 , wherein the VH region comprises the amino acid sequence shown in SEQ ID NO: 6 and the VL region comprises the amino acid sequence shown in SEQ ID NO: 5.

18. The FLT3 specific CAR of claim 5 , wherein the the FLT3 specific CAR comprises one or more of the following:

(i) the second intracellular signaling domain comprises a 4-1BB domain; and

(ii) the stalk domain is selected from the group consisting of: a CD8α hinge, an IgG1 hinge, and an FcγRIIIα hinge.

19. The FLT3 specific CAR of claim 6 , wherein the one or more epitopes is or are selected from the group consisting of:

(i) a CD52 epitope, a CD20 epitope, a CD3 epitope, a CD41 epitope, a CD25 epitope, a CD30 epitope, an EGFR epitope, a TNFα epitope, a VEGF epitope, a complement protein C5 epitope, a CD11a epitope, a CD33 epitope, an alpha-4 integrin epitope, an IgE Fc region epitope, an RSV protein F epitope, an IL-6 receptor epitope, a HER2 receptor epitope, an integrin α4β7epitope, a BAFF (B-cell activating factor) epitope, an IL-1β epitope, a RANKL epitope, a CTLA4 epitope, a CD34 epitope, an IL-12 epitope, an IL-23 epitope, and combinations thereof;

(ii) an epitope specifically recognized by alemtuzumab, ibritumomab tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10, or ustekinumab; and

(iii) a CD20 epitope.

20. The FLT3 specific CAR of claim 19 , wherein the FLT3 specific CAR comprises a CD20 epitope comprising the amino acid sequence shown in SEQ ID NO: 229.

21. The FLT3 specific CAR of claim 7 , wherein the FLT3 specific CAR comprises the amino acid sequence shown in SEQ ID NO: 235.

22. The FLT3 specific CAR of claim 7 , wherein the FLT3 specific CAR comprises the amino acid sequence shown in SEQ ID NO: 236.

23. The FLT3 specific CAR of claim 8 , wherein the FLT3 specific CAR comprises a third polypeptide comprising a third transmembrane domain fused to an intracellular signaling domain from a co-stimulatory molecule, wherein the third transmembrane domain comprises a transmembrane domain from the γ or β chain of FcεRI.

24. The engineered immune cell of claim 11 , wherein (i) the suicide polypeptide is RQR8, or (ii) the immune checkpoint protein is programmed death-1 (PD-1), or (iii) the suicide polypeptide is RQR8 and the immune checkpoint protein is programmed death-1 (PD-1).

Assignments (9)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 31, 2020
From: SASU, BARBRA JOHNSON; DETTLING, DANIELLE ELIZABETH; SOMMER, CESAR ADOLFO; YEUNG, YIK ANDY
To: PFIZER INC.
Reel/Frame 052275/0631 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 31, 2020
From: HAMZE, MOUSTAFA MARC
To: CELLECTIS
Reel/Frame 052275/0768 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 31, 2020
From: CELLECTIS
To: PFIZER INC.
Reel/Frame 052275/0836 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2019
From: DETTLING, DANIELLE ELIZABETH; YEUNG, YIK ANDY; POULSEN, KRISTIAN TODD
To: RINAT NEUROSCIENCE CORP.
Reel/Frame 051133/0312 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2019
From: SASU, BARBRA JOHNSON; DETTLING, DANIELLE ELIZABETH; SOMMER, CESAR ADOLFO; YEUNG, YIK ANDY
To: PFIZER INC.
Reel/Frame 051133/0231 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2019
From: DETTLING, DANIELLE ELIZABETH; YEUNG, YIK ANDY; POULSEN, KRISTIAN TODD; KRISHNAMOORTHY, VEENA; SOMMER, CESAR ADOLFO
To: PFIZER INC.
Reel/Frame 051133/0405 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2019
From: RINAT NEUROSCIENCE CORP.
To: PFIZER INC.
Reel/Frame 051133/0396 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2019
From: HAMZE, MOUSTAFA MARC
To: CELLECTIS
Reel/Frame 051133/0254 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2019
From: CELLECTIS
To: PFIZER INC.
Reel/Frame 051133/0276 →
Continuity (4)
Provisional Application 62660908 · Apr 20, 2018
Provisional Application 62514634 · Jun 2, 2017
Provisional Application 62514574 · Jun 2, 2017
Related Publication 20230181634A1 · Jun 15, 2023
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