Granted Patent B2

US 12,624,081 · App. 17/370,655 · Granted May 12, 2026

Inventors: Avery D. Posey (Philadelphia, PA); Carl H. June (Merion Station, PA)

Assignee: THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

C07K14/7051A61K40/11A61K40/31A61K40/4211A61K40/4257A61P35/00C07K14/70507C07K14/70517C07K14/70596A61K31/675A61K31/7076A61K45/06A61K2239/31A61K2239/38A61K2239/48A61K2239/49A61K2239/54A61K2239/55A61K2239/59

Abstract

Claims (29)

1 . A modified immune cell comprising:

(a) a chimeric antigen receptor (CAR) that specifically binds MUC1 on a target cell, wherein the CAR comprises a MUC1-specific antigen binding domain, a transmembrane domain, a costimulatory signaling domain, and an intracellular signaling domain of CD3 zeta, and wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO: 47; and

(b) a switch receptor comprising an extracellular domain of a signaling protein associated with a negative signal, a transmembrane domain, and an intracellular domain of a signaling protein associated with a positive signal;

wherein the extracellular domain and the intracellular domain are respectively selected from PD-1 and CD28, PD-1 A132L and CD28, PD-1 and 4-1BB, PD-1 A132L and 4-1BB, PD-1 and IL12Rβ1, PD-1 A132L and IL12Rβ1, PD-1 and IL12Rβ2, PD-1 A132L and IL12Rβ2, TGFβRII and IL12Rβ1, TGFβRII and IL12Rβ2, TGFβRII and CD28, or TIM3 and CD28; and

wherein the switch receptor is able to switch a negative signal to a positive signal upon activation, thereby enhancing an immune response.

2 . The modified immune cell of claim 1 , wherein the switch receptor is PD1-CTM-CD28 or TGFβR-IL12Rβ1.

3 . The modified immune cell of claim 1 , wherein the modified cell is a modified natural killer (NK) cell, a modified natural killer T (NKT) cell, or a modified T cell.

4 . The modified immune cell of claim 3 , wherein the modified immune cell is a modified T cell.

5 . The modified immune cell of claim 1 , wherein:

the switch receptor comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 78, 80, 82, 84, 86, 88, 90, and 92.

6 . An isolated nucleic acid comprising:

(a) a first nucleic acid sequence encoding a chimeric antigen receptor (CAR) that specifically binds MUC1 on a target cell, wherein the CAR comprises a MUC1-specific antigen binding domain, a transmembrane domain, a costimulatory signaling domain, and an intracellular signaling domain of CD3 zeta, and wherein the first nucleic acid sequence comprises SEQ ID NO: 46; and

(b) a second nucleic acid sequence encoding a switch receptor comprising an extracellular domain of a signaling protein associated with a negative signal, a transmembrane domain, and an intracellular domain of a signaling protein associated with a positive signal;

wherein the extracellular domain and the intracellular domain are respectively selected from PD-1 and CD28, PD-1 A132L and CD28, PD-1 and 4-1BB, PD-1 A132L and 4-1BB, PD-1 and IL12Rβ1, PD-1 A132L and IL12Rβ1, PD-1 and IL12Rβ2, PD-1 A132L and IL12Rβ2, TGFβRII and IL12Rβ1, TGFβRII and IL12Rβ2, TGFβRII and CD28, or TIM3 and CD28;

wherein the switch receptor is able to switch the negative signal to the positive signal upon activation, thereby enhancing an immune response; and

wherein the first and second nucleic acid sequences are separated by a nucleic acid sequence encoding a self-cleaving peptide.

7 . The isolated nucleic acid of claim 6 , wherein and the second nucleic acid sequence comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 79, 81, 83, 85, 87, 89, 91, and 93.

8 . An expression construct comprising the isolated nucleic acid of claim 6 .

9 . A method for generating a modified immune cell, comprising introducing into an immune cell the isolated nucleic acid of claim 6 .

10 . A method of treating a MUC1 associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising the modified immune of claim 1 .

11 . The method of claim 10 , further comprising:

(a) administering to the subject a lymphodepleting chemotherapy; and/or

(b) administering to the subject a cytokine release syndrome (CRS) management regimen.

12 . The method of claim 11 , wherein the lymphodepleting chemotherapy comprises administering to the subject a therapeutically effective amount of cyclophosphamide, and a therapeutically effective amount of fludarabine.

13 . The method of claim 10 , wherein the MUC1-associated cancer is:

(a) selected from the group consisting of multiple myeloma, non-small cell lung cancer, breast cancer, pancreatic adenocarcinoma, ovarian, and fallopian tube cancer;

and/or

(b) characterized by abnormal glycosylation of MUC1.

14 . The method of claim 13 , wherein the breast cancer is selected from the group consisting of a hormone receptor-positive breast cancer, a hormone receptor-negative breast cancer, an estrogen receptor-negative breast cancer, a progesterone receptor-negative breast cancer, triple negative breast cancer, and a Her2 receptor-negative breast cancer.

Assignments (1)

Continuity (4)

References Cited (210)