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US 2023/0414752 A1Published application
Constrained conditionally activated binding proteins
AssigneeTakeda Pharmaceutical Company Limited
InventorsChad May, Robert B. BuBridge, 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.
Claims17
-51. (canceled)
A protein comprising from N- to C-terminal:
- a) a first single domain antigen binding domain (sdABD) that binds to a human tumor target antigen (TTA) (sdABD-TTA);
- b) a first domain linker;
- c) a constrained Fv domain comprising;
- i) a first variable heavy (VH) domain comprising a vhCDR1, vhCDR2 and vhCDR3;
- ii) a constrained non-cleavable linker (CNCL);
- and
- iii) a first variable light (VL) domain comprising vlCDR1, vlCDR2, and clCDR3;
- 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 (VL) domain;
- ii) a non-cleavable linker (NCL);
- and
- iii) a first pseudo heavy variable (VH) domain;
- h) a third domain linker;
- and
- i) a third sdABD that binds to human serum albumin;
- wherein the first variable heavy domain and the first variable light domain are capable of binding human CD3, but the constrained Fv domain does not bind CD3;
- wherein the first variable heavy domain and the first pseudo variable light domain intramolecularly associate to form an inactive Fv;
- and wherein the first variable light domain and the first pseudo variable heavy domain intramolecularly associate to form an inactive Fv.
18 more elements
A pair of polypeptides comprising:
- a) a first polypeptide comprising a first target antigen binding domain linked using a first domain linker to a first single chain Fv (scFv) domain directed to a CD-3 antigen, wherein the first polypeptide further comprises a half-life extension domain, and
- b) a second polypeptide comprising a second target antigen binding domain linked using a second domain linker to a second single chain Fv (scFv) domain directed to a CD-3 antigen, wherein the second polypeptide further comprises a half-life extension domain;
- wherein the first scFv domain comprises an inactive VH domain and an active VL domain joined through a first cleavable linker between the inactive VH domain and the active VL domain, the inactive VH domain and the active VL domain interact to form a first VH/VL pair that does not specifically bind the CD-3 antigen;
- and
- wherein the second scFv domain comprises an active VH domain and an inactive VL domain joined through a second cleavable linker between the active VH domain and the inactive VL domain, the active VH domain and the inactive VL domain interact to form a second VH/VL pair that does not specifically bind the CD-3 antigen.
2 more elements
Dependencies are inferred from the claim text.