Binding site for conditional activation of immunoglobulin molecules

Abstract

To provide a binding portion including a non-CDR loop for masking bond of binding molecule to the target, CDR for binding a bulk serum protein, a conditionally active target binding protein containing a binding portion, a pharmaceutical composition containing the binding protein, and a method for using such a preparation.SOLUTION: Provided is a conditionally active binding protein, where the binding protein includes: a first target antigen-binding domain that includes a binding portion including a non-CDR loop; a cleavable linker; and an immunoglobulin molecule binding to CD3ε domain, in which the non-CDR loop includes a first target antigen-binding domain including a binding site specific to the first target antigen-binding domain; and a second target antigen-binding domain, where the binding site can mask bond of the first target antigen-binding domain to the target.SELECTED DRAWING: Figure 7

Claims

1. A conditionally active binding protein, wherein the conditionally active binding protein is (a) A binding portion (M) comprising a single-domain antibody (sdAb) that binds to human serum albumin, wherein the sdAb comprises the amino acid sequence of amino acid residues 1-124 of SEQ ID NO: 54, (b) A cleavable linker (L) including a cleavage site recognized by a protease, (c) A first target antigen-binding domain (T1) containing an immunoglobulin molecule that binds to CD3ε, (d) Second target antigen binding domain (T2), Includes, Here, the binding portion (M) can mask the binding of the first target antigen-binding domain (T1) to CD3ε, and here, when the cleavage site is cleaved within the tumor microenvironment, the conditionally active binding protein is activated by the separation of the binding portion (M). A conditionally active binding protein.

2. The conditionally active binding protein according to claim 1, wherein the second target antigen-binding domain (T2) comprises an immunoglobulin molecule that binds to a tumor antigen.

3. The tumor antigens include EpCAM, EGFR, HER-2, HER-3, c-Met, FoLR, PSMA, CD38, BCMA, CEA, 5T4, AFP, B7-H3, CDH-6, CAIX, CD117, CD123, CD138, CD166, CD19, CD20, CD 205, CD22, CD30, CD33, CD352, CD37, CD44, CD52, CD56, CD70, CD71, CD74, C D79b, DLL3, EphA2, FAP, FGFR2, FGFR3, GPC3, gpA33, FLT-3, gpNMB, HPV-16 E6, HPV-16 A conditionally active binding protein according to claim 2, comprising E7, ITGA2, ITGA3, SLC39A6, MAGE, mesothelin (MSLN), Muc1, Muc16, NaPi2b, Nectin-4, CDH-3, CDH-17, EPHB2, ITGAV, ITGB6, NY-ESO-1, PRLR, PSCA, PTK7, ROR1, SLC44A4, SLITRK5, SLITRK6, STEAP1, TIM1, Trop2, or WT1.

4. The conditionally active binding protein according to any one of claims 1 to 3, wherein the cleavable linker (L) comprises one amino acid sequence of SEQ ID NO: 1-42, 53, 58-62, or 909.

5. (a) The tumor antigen comprises EGFR, and the second target antigen-binding domain (T2) comprises an anti-EGFR domain comprising one amino acid sequence of either SEQ ID NO: 55 or 737-785. (b) The tumor antigen comprises PSMA, and the second target antigen-binding domain (T2) comprises an anti-PSMA domain comprising any one amino acid sequence of SEQ ID NO: 57-73. (c) The tumor antigen comprises BCMA, and the second target antigen-binding domain (T2) comprises an anti-BCMA domain comprising any one amino acid sequence of SEQ ID NO: 91-214. (d) The tumor antigen comprises mesothelin (MSLN), and the second target antigen-binding domain (T2) comprises an anti-MSLN domain comprising any one amino acid sequence of SEQ ID NO: 215-258. (e) The tumor antigen comprises DLL3, and the second target antigen-binding domain (T2) comprises an anti-DLL3 domain comprising any one amino acid sequence of SEQ ID NO: 306-736, or (f) The conditionally active binding protein according to any one of claims 1 to 4, wherein the tumor antigen comprises EpCAM, and the second target antigen binding domain (T2) comprises an anti-EpCAM domain comprising one amino acid sequence of SEQ ID NO: 804-841, 897, or 898.

6. The use of a conditionally active binding protein according to any one of claims 1-5 in the manufacture of a drug for treating cancer in a subject requiring treatment.

7. The use according to claim 6, wherein the cancer is associated with the expression of EpCAM, EGFR, PSMA, BCMA, DLL3, or mesothelin (MSLN).

8. A polynucleotide encoding a conditionally active binding protein according to any one of claims 1 to 7.

9. A vector comprising the polynucleotide described in claim 8.

10. A host cell comprising the polynucleotide described in claim 8 or the vector described in claim 9.

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