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First Polypetide US 20200148771A1 INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0148771 A1 BAEUERLE et al. (43 ) Pub . Date : May 14 , 2020 ( 54 ) INDUCIBLE MONOVALENT ANTIGEN Publication Classification BINDING PROTEIN (51 ) Int. Ci. ( 71 ) Applicant: Harpoon Therapeutics , Inc. , South CO7K 16/28 (2006.01 ) (52 ) U.S. CI. San Francisco , CA (US ) CPC CO7K 16/2818 ( 2013.01 ) ; CO7K 16/2878 (72 ) Inventors : Patrick BAEUERLE , South San (2013.01 ) ; CO7K 2317/526 ( 2013.01 ) ; CO7K Francisco , CA (US ) ; Holger WESCHE , 2317/524 ( 2013.01) ; CO7K 2317/75 ( 2013.01 ) ; South San Francisco , CA (US ) CO7K 2317/565 ( 2013.01) ; CO7K 2317/35 ( 2013.01) ; CO7K 2317/622 (2013.01 ) ; COOK ( 21 ) Appl. No.: 16 /489,523 2317/92 ( 2013.01 ) ; CO7K 2319/50 (2013.01 ) ( 22 ) PCT Filed : Feb. 28 , 2018 (57 ) ABSTRACT ( 86 ) PCT No .: PCT /US2018 / 020307 Disclosed herein are inducible monovalent target -binding $ 371 ( c ) ( 1 ) , proteins which are activated upon protease cleavage . Phar (2 ) Date : Aug. 28 , 2019 maceutical compositions comprising the binding proteins Related U.S. Application Data disclosed herein and methods of using such formulations are ( 60 ) Provisional application No. 62/ 465,000 , filed on Feb. further provided . 28 , 2017 . Specification includes a Sequence Listing . scFv1 SCFVZ Anti - Target binding domain Secondpolypeptide Firstpolypeptide CH2 - Fc1 CH2 -Fc2 CH2 - Fc1 CH2 - Fc2 CH3 - Fc1 B CH3 -Fc2 Proteolytic cleavage CH3 - Fc1 CH3 - Fc2 heterodimer FC1 - Fc2 heterodimer Inactive Active Patent Application Publication May 14 , 2020 Sheet 1 of 5 US 2020/0148771 A1 Fig. 1 schyi scFv2 Anti- Target binding domain polypeptideSecond VHH VI Firstpolypeptide CH2 -Fc1 CH2 - Fc2 CH2 - Fc1 CH2 - Fc2 CH3 - Fc1 CH3 - FcZ Proteolytic cleavage CH3 - Fc1 CH3- Fc2 heterodimer FC1 - FC2 heterodimer Inactive Active Patent Application Publication May 14 , 2020 Sheet 2 of 5 US 2020/0148771 A1 Fig . 2 Inert VL Protezse - clesvable Protease FC prwis Prodrug Active Drug Patent Application Publication May 14 , 2020 Sheet 3 of 5 US 2020/0148771 A1 Fig . 3 Anti - CD40 Anti- CTLA4 ProMonoMabs ProMonoMabs Dace Seli Treme Antibody *** + ?? option 32 motions Protease 66 Patent Application Publication May 14 , 2020 Sheet 4 of 5 US 2020/0148771 A1 SetProtocowab(activated ma Selictelumab(ant-CD40) Coronkacw Tremetiena(anti-CTLA4} Concentration 3 ) A450 ( Binding CTLA4 4.Fig ) 4450( Binding C040 kockets-15 ma 1 WE Dacenzurabfani-C040) ???? 38 Cmontsion Ipilimutsb(BILA4 CurvedSize am ) A450 ( Binding GOO ) A460 ( Brxding OTLA4 2888 Patent Application Publication May 14 , 2020 Sheet 5 of 5 US 2020/0148771 A1 -SelProfvionoMabactivated() 1000 100 Crosslinked Concentration(nu ) OD640( Signaling CD40 5.Fig SeliProMano-Mabactivated(, 10 Concentration(nka) Non-crosslinked ma 38 0.2 ) OD640( Signaling CD40 US 2020/0148771 A1 May 14 , 2020 INDUCIBLE MONOVALENT ANTIGEN [ 0010 ] In some embodiments , the iVL comprises a BINDING PROTEIN CDRL1, CDRL2 , and CDRL3 , and the at least one protease cleavage site of the iVL is located within the CDRL1 , CROSS -REFERENCE CDRL2 , or CDRL3 . In some embodiments , the iVH com prises a CDRH1, CDRH2 , and CDRH3, and the at least one [0001 ] This application claims the benefit of U.S. Provi protease cleavage site of the iVH is located within the sional Application No. 62/ 465,000 , filed Feb. 28 , 2017 , CDRH1, CDRH2, or CDRH3. In some embodiments , the which is incorporated by reference herein in its entirety . first polypeptide chain comprises a further protease cleavage site , and wherein the second polypeptide comprises a further INCORPORATION BY REFERENCE protease cleavage site . In some embodiments , the further [ 0002 ] All publications, patents , and patent applications protease cleavage site of the first polypeptide chain is mentioned in this specification are herein incorporated by located within the Ll or the Ll' , and the further protease reference to the same extent as if each individual publica cleavage site of the second polypeptide chain is located tion , patent, or patent application was specifically and indi within the L6 or the L6 '. In some embodiments , the Fc1 and vidually indicated to be incorporated by reference , and as if Fc2 each independently comprise one or more amino acid set forth in their entireties . substitutions favoring formation of a heterodimeric Fc region . In some embodiments , the CH3 domain of the Fc1 BACKGROUND OF THE INVENTION comprises a substitution of an amino acid with a negatively [ 0003] The present disclosure provides an inducible mon charged amino acid , and the CH3 domain of the Fc2 ovalent target -binding protein which are activated upon comprises a substitution of an amino acid with a positively protease cleavage, and can be used for diagnosing and charged amino acid . In some embodiments , the CH3 domain treating cancers. of the Fcl comprises a substitution of an amino acid with a positively charged amino acid , and the CH3 domain of the SUMMARY OF THE INVENTION Fc2 comprises a substitution of an amino acid with a [0004 ] In one embodiment is provided , an inducible mon negatively charged amino acid . In some embodiments , the ovalent target - binding protein , wherein the protein com iVH and the iVL each independently comprise one or more prises a first polypeptide chain and a second polypeptide mutations that prohibit target binding of said domains . In chain , some embodiments , the VH , iVL , and the L1 or the Ll' of [0005 ] the first polypeptide chain comprising : a VH the first polypeptide form a scFv. In some embodiments , the target- binding domain (VH ) , an inactive VL domain VL , IVH , and the L6 or the L6 ' of the second polypeptide ( VL ) that binds to the VH domain , a linker (L1 ) , and form a scFv . a first monomeric Fc domain (Fcl ) comprising a CH3 [0011 ] In one embodiment is provided , an inducible mon and a CH2 domain ; ovalent target - binding protein , wherein the protein com [0006 ] the second polypeptide chain comprising : a VL prises a first scFv ( scFv1 ) and a second scFv ( scFv2 ) , and a target- binding domain (VL ) , an inactive VH domain first (Fc1 ) and a second ( Fc2 ) monomeric Fc domain , each ( VH ) that binds to the VL domain , a linker ( L6 ) , a comprising a CH2 domain and a CH3 domain , second monomeric Fc domain (Fc2 ) comprising a CH3 [0012 ] the scFv1 comprising : a VH target -binding and a CH2 domain ; domain (VH ) , an inactive VL domain ( VL ) that binds wherein the iVL and the iVH each comprise at least one to the VH domain , and a (L1 ) ; protease cleavage site , wherein upon activation by protease [0013 ] the scFv2 comprising: a VL target -binding cleavage of the at least one protease cleavage site of both the domain ( VL ), an inactive VH domain ( iVH ) that binds iVL and the iVH , the VH and the VL associate to form an to the VL domain , and a linker (L6 ) ; active target- binding domain , and wherein the CH3 domains wherein the scFv1 and the scFv2 each comprise at least one of the Fcl and Fc2 form a heterodimer . protease cleavage site , wherein upon activation by protease [ 0007] In one embodiment is provided , An inducible mon cleavage of the protease cleavage sites , the VH and the VL ovalent target - binding protein , wherein the protein com associate to form an active target -binding domain , and prises a first polypeptide chain and a second polypeptide wherein the Fcl and the Fc2 form a Fc region comprising a chain , heterodimeric CH3 domain . [0008 ] the first polypeptide chain comprising : a VL target- binding domain (VL ) , an inactive VH domain [0014 ] In one embodiment is provided , an inducible mon ( iVH ) that binds to the VL domain , a linker (L1 ' ) , and ovalent target -binding protein , wherein the protein com a first monomeric Fc domain (Fc1 ) comprising a CH3 prises a first scFv (scFvl ) and a second scFv (scFv2 ) , and a and a CH2 domain ; first (Fcl ) and a second ( Fc2 ) monomeric Fc domain , each [ 0009 ] the second polypeptide chain comprising: a VH comprising a CH2 domain and a CH3 domain , target- binding domain (VH ) , an inactive VL domain [ 0015 ] the scFv1 comprising: a VL target -binding ( VL ) that binds to the VH domain , a linker (L6 ') , a domain (VL ) , an inactive VH domain ( iVH ) that binds second monomeric Fc domain (Fc2 ) comprising a CH3 to the VL domain , and a linker (L1 ' ) ; and a CH2 domain ; [0016 ] the scFv2 comprising: a VH target- binding wherein the iVH and the iVL each comprise at least one domain (VH ) , an inactive VL domain (AVL ) that binds protease cleavage site , wherein upon activation by protease to the VH domain , and a linker (L6 ') ; cleavage of the at least one protease cleavage site of both wherein the scFv1 and the scFv2 each comprise at least one iVH and the iVL , the VL and the VH associate to form an protease cleavage site , wherein upon activation by protease active target- binding domain , and wherein the CH3 domains cleavage of the at least one protease cleavage site of both the of the Fcl and the Fc2 form a heterodimer. scFv1 and the scFv2 , the VL and the VH associate to form US 2020/0148771 A1 May 14 , 2020 2 an active target -binding domain , and wherein the Fcl and [0018 ] One embodiment provides an inducible monova the Fc2 form a Fc region comprising a heterodimeric CH3 lent target -binding protein , wherein the protein comprises a domain . first polypeptide chain and a second polypeptide chain , [ 0019 ] the first polypeptide chain comprising : a VH [ 0017 ] In some embodiments , the iVL comprises a target- binding domain ( VH ) , an inactive VL domain CDRL1, CDRL2 , and CDRL3 , and the at least one protease ( VL ) that binds to the VH domain , a linker (L1 ) , and cleavage site of the iVL is located within the CDRLI , a first monomeric Fc domain (Fc1 ) comprising a CH3 CDRL2 , or CDRL3 .
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