Receptors providing targeted costimulation for adoptive cell therapy
OwnerJohn Bridgeman, Robert Hawkins +3inventors
InventorsJohn Bridgeman, Robert Hawkins, Ruben Rodriguez, Gray Kueberuwa, Milena Kalaitsidou
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Abstract
Some embodiments provided herein are chimeric costimulatory antigen receptor (CoStAR), useful in adoptive cell therapy (ACT), and cells comprising the CoStAR. In some embodiments, the CoStAR can act as a modulator of cellular activity enhancing responses to defined antigens. In some embodiments, CoStAR and/or fusion proteins, nucleic acids encoding the CoStAR and therapeutic uses thereof are also provided.
Claims30
1-43. (canceled)
A chimeric costimulatory antigen receptor (CoStAR) which comprises:
- an extracellular binding domain that binds to mesothelin (MSLN);
- a transmembrane domain;
- a CD28 signaling domain, wherein the CD28 signaling domain comprises the amino acid sequence of SEQ ID NO:
- 25;
- and
- a CD40 signaling domain, wherein the CD40 signaling domain comprises the amino acid sequence of SEQ ID NO:
- 32,
- wherein the extracellular binding domain comprises any one of:
- (a) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 186, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 186, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 186, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 186, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 186, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 186;
- (b) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 187, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 187, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 187, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 187, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 187, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 187;
- (c) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 188, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 188, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 188, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 188, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 188, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 188;
- (d) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 189, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 189, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 189, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 189, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 189, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 189;
- (e) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 190, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 190, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 190, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 190, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 190, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 190;
- (f) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 191, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 191, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 191, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 191, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 191, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 191;
- (g) a VH that is a VH in SEQ ID NO:
- 186, and a VL that is a VL in SEQ ID NO:
- 186;
- (h) a VH that is a VH in SEQ ID NO:
- 187, and a VL that is a VL in SEQ ID NO:
- 187;
- (i) a VH that is a VH in SEQ ID NO:
- 188, and a VL that is a VL in SEQ ID NO:
- 188;
- (j) a VH that is a VH in SEQ ID NO:
- 189, and a VL that is a VL in SEQ ID NO:
- 189;
- (k) a VH that is a VH in SEQ ID NO:
- 190, and a VL that is a VL in SEQ ID NO:
- 190;
- or
- (l) a VH that is a VH in SEQ ID NO:
- 191, and a VL that is a VL in SEQ ID NO:
- 191.
A cell which expresses a CoStAR, the CoStAR comprising:
- an extracellular binding domain that binds to mesothelin (MSLN);
- a CD28 signaling domain, wherein the CD28 signaling domain comprises the amino acid sequence of SEQ ID NO:
- 25;
- and
- a CD40 signaling domain, wherein the CD40 signaling domain comprises the amino acid sequence of SEQ ID NO:
- 32,
- wherein the extracellular binding domain comprises any one of:
- (a) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 186, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 186, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 186, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 186, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 186, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 186;
- (b) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 187, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 187, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 187, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 187, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 187, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 187;
- (c) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 188, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 188, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 188, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 188, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 188, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 188;
- (d) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 189, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 189, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 189, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 189, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 189, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 189;
- (e) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 190, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 190, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 190, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 190, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 190, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 190;
- (f) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 191, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 191, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 191, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 191, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 191, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 191;
- (g) a VH that is a VH in SEQ ID NO:
- 186, and a VL that is a VL in SEQ ID NO:
- 186;
- (h) a VH that is a VH in SEQ ID NO:
- 187, and a VL that is a VL in SEQ ID NO:
- 187;
- (i) a VH that is a VH in SEQ ID NO:
- 188, and a VL that is a VL in SEQ ID NO:
- 188;
- (j) a VH that is a VH in SEQ ID NO:
- 189, and a VL that is a VL in SEQ ID NO:
- 189;
- (k) a VH that is a VH in SEQ ID NO:
- 190, and a VL that is a VL in SEQ ID NO:
- 190;
- or
- (l) a VH that is a VH in SEQ ID NO:
- 191, and a VL that is a VL in SEQ ID NO:
- 191.
A fusion protein, wherein the fusion protein comprises:
- i. a first sequence, wherein the first sequence comprises one or more of:
- a. a HCDR1 that is an HCDR1 in SEQ ID NO:
- 186, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 186, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 186, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 186, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 186, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 186;
- b. a HCDR1 that is an HCDR1 in SEQ ID NO:
- 187, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 187, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 187, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 187, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 187, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 187;
- c. a HCDR1 that is an HCDR1 in SEQ ID NO:
- 188, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 188, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 188, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 188, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 188, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 188;
- d. a HCDR1 that is an HCDR1 in SEQ ID NO:
- 189, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 189, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 189, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 189, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 189, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 189;
- e. a HCDR1 that is an HCDR1 in SEQ ID NO:
- 190, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 190, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 190, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 190, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 190, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 190;
- f. a HCDR1 that is an HCDR1 in SEQ ID NO:
- 191, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 191, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 191, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 191, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 191, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 191;
- g. a VH that is a VH in SEQ ID NO:
- 186, and a VL that is a VL in SEQ ID NO:
- 186;
- h. a VH that is a VH in SEQ ID NO:
- 187, and a VL that is a VL in SEQ ID NO:
- 187;
- i. a VH that is a VH in SEQ ID NO:
- 188, and a VL that is a VL in SEQ ID NO:
- 188;
- j. a VH that is a VH in SEQ ID NO:
- 189, and a VL that is a VL in SEQ ID NO:
- 189;
- k. a VH that is a VH in SEQ ID NO:
- 190, and a VL that is a VL in SEQ ID NO:
- 190;
- or
- (a) a VH that is a VH in SEQ ID NO:
- 191, and a VL that is a VL in SEQ ID NO:
- 191;
- ii. a second sequence that is a transmembrane domain;
- iii. a third sequence that comprises the amino acid sequence of SEQ ID NO:
- 25;
- and
- iv. a fourth sequence that comprises the amino acid sequence of SEQ ID NO:
- 32, wherein the first sequence is linked to the second sequence, wherein the second sequence is linked to the third sequence, and wherein the third sequence is linked to the fourth sequence.
A method of cell therapy comprising:
- a) identifying a subject, wherein the subject has cancer that expresses MSLN;
- and
- b) administering any a CoStAR that comprises:
- an extracellular binding domain that binds to mesothelin (MSLN),
- a transmembrane domain,
- a CD28 signaling domain that comprises the amino acid sequence of SEQ ID NO:
- 25;
- and
- a CD40 signaling domain, wherein the CD40 signaling domain comprises the amino acid sequence of SEQ ID NO:
- 32,
- wherein the extracellular binding domain is linked to the transmembrane domain, wherein the transmembrane domain is linked to the CD28 signaling domain, wherein the CD28 signaling domain is linked to the CD40 domain, and
- wherein the extracellular binding domain comprises any one or more of:
- (a) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 186, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 186, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 186, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 186, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 186, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 186;
- (b) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 187, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 187, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 187, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 187, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 187, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 187;
- (c) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 188, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 188, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 188, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 188, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 188, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 188;
- (d) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 189, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 189, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 189, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 189, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 189, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 189;
- (e) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 190, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 190, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 190, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 190, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 190, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 190;
- (f) a HCDR1 that is an HCDR1 in SEQ ID NO:
- 191, a HCDR2 that is an HCDR2 in SEQ ID NO:
- 191, a HCDR3 that is an HCDR3 in SEQ ID NO:
- 191, a LCDR1 that is an LCDR1 in SEQ ID NO:
- 191, a LCDR2 that is an LCDR2 in SEQ ID NO:
- 191, and LCDR3 that is an LCDR3 in SEQ ID NO:
- 191;
- (g) a VH that is a VH in SEQ ID NO:
- 186, and a VL that is a VL in SEQ ID NO:
- 186;
- (h) a VH that is a VH in SEQ ID NO:
- 187, and a VL that is a VL in SEQ ID NO:
- 187;
- (i) a VH that is a VH in SEQ ID NO:
- 188, and a VL that is a VL in SEQ ID NO:
- 188;
- (j) a VH that is a VH in SEQ ID NO:
- 189, and a VL that is a VL in SEQ ID NO:
- 189;
- (k) a VH that is a VH in SEQ ID NO:
- 190, and a VL that is a VL in SEQ ID NO:
- 190;
- or
- (1) a VH that is a VH in SEQ ID NO:
- 191, and a VL that is a VL in SEQ ID NO:
- 191.
Dependencies are inferred from the claim text.