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US 2024/0199739 A1Published application
Constrained conditionally activated binding proteins
AssigneeTakeda Pharmaceutical Company Limited
InventorsChad May, Robert B. DuBridge, Maia Vinogradova, Anand Panchal
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Abstract
The invention relates to COnditional Bispecific Redirected Activation constructs, or COBRAs, that are administered in an active pro-drug format. Upon exposure to tumor proteases, the constructs are cleaved and activated, such that they can bind both tumor target antigens (TTAs) as well as CD3, thus recruiting T cells expressing CD3 to the tumor, resulting in treatment. In some embodiments, the tumor target antigen is B7H3.
Claims23
-22. (canceled)
A fusion protein comprising, from N- to C-terminal:
- a) a first sdABD-TTA;
- b) a first domain linker;
- c) a constrained Fv domain comprising:
- i) a first variable heavy domain comprising a vhCDRI, vhCDR2 and vhCDR3;
- ii) a constrained non-cleavable linker (CNCL);
- and
- iii) a first variable light domain comprising vlCDRI, vlCDR2 and vlCDR3;
- d) a second domain linker;
- e) a second sdABD-TTA;
- f) a cleavable linker (CL);
- g) a constrained pseudo Fv domain comprising:
- i) a first pseudo light variable domain;
- ii) a non-cleavable linker (NCL);
- and
- iii) a first pseudo heavy variable domain;
- h) a third domain linker;
- and
- i) a third sdABD that binds to human serum albumin;
- wherein said first variable heavy domain and said first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3;
- said first variable heavy domain and said first pseudo variable light domain intramolecularly associate to form an inactive Fv;
- said first variable light domain and said first pseudo variable heavy domain intramolecularly associate to form an inactive Fv;
- and
- wherein at least one of said sdABD-TTA is a sdABD-Trop2, comprising:
- (i) a complementarity-determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:
- 78, a complementarity-determining region 2 (CDR2) comprising the amino acid sequence of SEQ ID NO:
- 79, and a complementarity-determining region 3 (CDR3) comprising the amino acid sequence of SEQ ID NO:
- 80;
- (ii) a CDR1 comprising the amino acid sequence of SEQ ID NO:
- 82, a CDR2 comprising the amino acid sequence of SEQ ID NO:
- 83, and a CDR3 comprising the amino acid sequence of SEQ ID NO:
- 84;
- (iii) a CDR1 comprising the amino acid sequence of SEQ ID NO:
- 86, a CDR2 comprising the amino acid sequence of SEQ ID NO:
- 87, and a CDR3 comprising the amino acid sequence of SEQ ID NO:
- 88;
- (iv) a CDR1 comprising the amino acid sequence of SEQ ID NO:
- 90, a CDR2 comprising the amino acid sequence of SEQ ID NO:
- 91, and a CDR3 comprising the amino acid sequence of SEQ ID NO:
- 92;
- (v) a CDR1 comprising the amino acid sequence of SEQ ID NO:
- 94, a CDR2 comprising the amino acid sequence of SEQ ID NO:
- 95, and a CDR3 comprising the amino acid sequence of SEQ ID NO:
- 96;
- or
- (vi) a CDR1 comprising the amino acid sequence of SEQ ID NO:
- 98, a CDR2 comprising the amino acid sequence of SEQ ID NO:
- 99, and a CDR3 comprising the amino acid sequence of SEQ ID NO:
- 100.
45 more elements
Dependencies are inferred from the claim text.