WO2021167885A1 - Cd137 binding molecules and uses thereof - Google Patents

Cd137 binding molecules and uses thereof Download PDF

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Publication number
WO2021167885A1
WO2021167885A1 PCT/US2021/018177 US2021018177W WO2021167885A1 WO 2021167885 A1 WO2021167885 A1 WO 2021167885A1 US 2021018177 W US2021018177 W US 2021018177W WO 2021167885 A1 WO2021167885 A1 WO 2021167885A1
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Prior art keywords
seq
mab
binding
cdr
cancer
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English (en)
French (fr)
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Alexey Yevgenyevich Berezhnoy
Gundo Diedrich
Paul A. Moore
Ezio Bonvini
Kalpana SHAH
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Macrogenics Inc
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Macrogenics Inc
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Priority to IL295434A priority Critical patent/IL295434A/en
Priority to KR1020227031081A priority patent/KR20220144821A/ko
Priority to AU2021224787A priority patent/AU2021224787A1/en
Priority to MX2022010228A priority patent/MX2022010228A/es
Priority to BR112022015656A priority patent/BR112022015656A2/pt
Priority to CN202180013446.6A priority patent/CN115279403A/zh
Priority to CA3170330A priority patent/CA3170330A1/en
Priority to JP2022548145A priority patent/JP7745556B2/ja
Priority to EP21757515.8A priority patent/EP4106813A4/en
Application filed by Macrogenics Inc filed Critical Macrogenics Inc
Priority to US17/798,285 priority patent/US12435155B2/en
Priority to TW114121532A priority patent/TW202542198A/zh
Priority to TW110106005A priority patent/TWI889761B/zh
Publication of WO2021167885A1 publication Critical patent/WO2021167885A1/en
Anticipated expiration legal-status Critical
Priority to ZA2022/10020A priority patent/ZA202210020B/en
Priority to JP2025152980A priority patent/JP2025186381A/ja
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Definitions

  • the invention additionally concerns the embodiment of all such CD137 Binding Molecules wherein the Fc Region is a variant Fc Region that comprises one or more amino acid modifications that reduces the affinity of the variant Fc Region for an Fc ⁇ R and/or enhances the serum half-life, and more particularly, wherein the modifications comprise at least one amino acid substitution selected from the group consisting of: (A) L234A; L235A; (B) L234A and L235A; (C) M252Y; M252Y and S254T; (D) M252Y and T256E; (E) M252Y, S254T and T256E; or (F) K288D and H435K; wherein the numbering is that of the EU index as in Kabat.
  • the modifications comprise at least one amino acid substitution selected from the group consisting of: (A) L234A; L235A; (B) L234A and L235A; (C) M252Y; M252Y and S254T; (
  • the invention further concerns a method of enhancing the activity of a tumor targeting agent comprising administering the tumor target agent in combination with any of the above-described CD137 Binding Molecules, any of the above-described PD-L1 Binding Molecules, or any of the above-described pharmaceutical compositions.
  • the invention additionally concerns a method of treating a disease or condition associated with a suppressed immune system or characterized by the expression of a TA comprising administering to a subject in need thereof and of the above-described CD137 Binding Molecules, any of the above-described PD-L1 Binding Molecules, or any of the above-described pharmaceutical compositions.
  • Figures 1A-1D show tetravalent diabodies having four epitope-binding sites composed of two pairs of polypeptide chains, (i.e., four polypeptide chains in all).
  • One polypeptide of each pair possesses a CH2 and CH3 Domain, such that the associated chains form all or part of an Fc Region.
  • VL and VH Domains that recognize the same epitope are shown using the same shading or fill pattern.
  • the two pairs of polypeptide chains may be same.
  • the resulting molecule possesses four epitope- binding sites and is bispecific and bivalent with respect to each bound epitope.
  • Figure 1A shows an Fc diabody which contains a peptide Heterodimer-Promoting Domain comprising a cysteine residue.
  • Figure 1B shows an Fc diabody composed of two pairs of polypeptide chains each having an E-coil or K-coil Heterodimer-Promoting Domain (i.e., four polypeptide chains in all).
  • the wavy line (WWW) in this and all of the Figures providing schematic presentations of binding molecule domains represents one or more optional Heterodimer-Promoting Domains, that is/are present.
  • a cysteine residue may be present in a linker (main diagram) and/or in the Heterodimer-Promoting Domain (boxed).
  • the polypeptide chains comprising the VL and VH Domain further comprise a Heterodimer-Promoting Domain, shown here comprising a cysteine residue.
  • Figure 2 provides schematics of a representative covalently bonded binding molecule having four epitope-binding sites composed of five polypeptide chains. Two of the polypeptide chains possess a linker comprising a cysteine (which linker may comprise all or a portion of a hinge region) and a CH2 and CH3 Domain, such that the associated chains form an Fc Region that comprises all or part of an Fc Region.
  • the polypeptide chains comprising the linked VL and VH Domains further comprise a linker and a Heterodimer-Promoting Domain (further described in Figure 1B).
  • Figures 21A-21B show the ability of several representative PD-L1 x CD137 bispecific molecules: TRIDENT-A, TRIDENT-A6 comprising the VH/VL of CD137 MAB- 6 binding domain, or comparator molecules: TRIDENT-2, DUO-1 comprising the VH/VL of different CD137 binding domains, in combination with a representative TA x CD3 bispecific molecules (5T4 x CD3 diabody), to prevent or inhibit tumor growth or development of RKO colon carcinoma cells in vivo relative to a vehicle control in a murine PBMC-reconstituted xenograft model.
  • Representative data from a first study are plotted in Figure 21A, and from a second study in Figure 21B.
  • existing monoclonal antibodies and any other equivalent antibodies that are immunospecific for a desired pathogenic epitope can be sequenced and produced recombinantly by any means known in the art.
  • such an antibody is sequenced, and the polynucleotide sequence is then cloned into a vector for expression or propagation.
  • the sequence encoding the antibody of interest may be maintained in a vector in a host cell and the host cell can then be expanded and frozen for future use.
  • a Heterodimer- Promoting Domain in which one of the four tandem “E-coil” helical domains of SEQ ID NO:37 has been modified to contain a cysteine residue: EVAACEK-EVAALEK-EVAALEK- EVAALEK (SEQ ID NO:39) is utilized.
  • PD-L1 (also known as CD274 and B7-H1), is a 40 kDa transmembrane protein commonly expressed on the surface of T lymphocytes, B lymphocytes, DCs, macrophages and in non-blood cells.
  • PD-L1 also shows abnormally high expression in tumor cells, which is considered the main factor responsible for promoting the ability of tumor immune escape. Engagement of PD-L1 with its receptor, PD-1 on T cells activates the down-stream signaling of PD-1 receptor delivering a signal that inhibits the proliferation, cytokine generation and release, and cytotoxicity of T cells.
  • the amino acid sequences of the CDRHs of hPD-L1 MAB-2 VHx are: CDRH1 (SEQ ID NO:60): SYTMS CDRH2 (SEQ ID NO:61): YISIX 4 GGTTYYPDTVKG CDR H 3 (SEQ ID NO:62): X 8 GLPYYX 9 DY wherein: X4 is G or K; X8 is A or Q; and X9 is F or G
  • the amino acid sequence of hPD-L1 MAB-2 VLx is (SEQ ID NO:63) (CDRL residues are shown underlined): DIQMTQSPSS LSASVGDRVT ITCKASQDVN X 10 AVAWYQQKP GKAPKLLIYW ASTRHTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ HYNTPLTFGQ GTKVEIK wherein: X10 is E or T.
  • FIG. 2 illustrates the structure of such diabodies.
  • the VL1/VH1, VL2/VH2, and VL3/VH3 Domains may be the same or different so as to permit binding that is monospecific, bispecific or trispecific. However, as provided herein, these domains are selected so as to bind CD137 and a TA.
  • the VL and VH Domains of the polypeptide chains are selected so as to form VL/VH binding sites specific for a desired epitope.
  • the VL/VH binding sites formed by the association of the polypeptide chains may be the same or different so as to permit tetravalent binding that is monospecific, bispecific, trispecific or tetraspecific.
  • Fab-Type Binding Domains differ from Diabody-Type Binding Domain in that the two polypeptide chains that form a Fab-Type Binding Domain comprise only a single Epitope- Binding Domain, whereas the two polypeptide chains that form a Diabody-Type Binding Domain comprise at least two Epitope-Binding Domains.
  • ScFv-Type Binding Domains differ from Diabody-Type Binding Domain in that VL and VH Domains of the same polypeptide chain interact to form an Epitope-Binding Domain.
  • Fab-Type Binding Domains and ScFv-Type Binding Domains are distinct from Diabody-Type Binding Domain.
  • Such alternative second and fourth polypeptide chains of DART-A sometimes are composed of: SEQ ID NO:50 ⁇ SEQ ID NO:16 ⁇ SEQ ID NO:57 ⁇ SEQ ID NO:18 ⁇ SEQ ID NO:38.
  • Additional alternative DART-A first and third polypeptide chains may be employed in which the amino acid residues of SEQ ID NO:50 (CD137 MAB-6 VL1) are replaced with the amino acid residues of SEQ ID NO:55 (CD137 MAB-6 VL2), or SEQ ID NO:56 (CD137 MAB-6 VL3), and/or the amino acid residues of SEQ ID NO:57 (hPD-L1 MAB-2 VH1) are replaced with the amino acid residues of SEQ ID NO:67 (hPD-L1 MAB-2 VH2), SEQ ID NO:68 (hPD-L1 MAB-2 VH3), SEQ ID NO:69 (hPD-L1 MAB-2 VH4), SEQ ID NO:70 (hPD-L1 MAB-2 VH5), or
  • the first and third polypeptide chain of DART-A1 are composed of: SEQ ID NO:58 ⁇ SEQ ID NO:16 ⁇ SEQ ID NO:46 ⁇ SEQ ID NO:18 ⁇ SEQ ID NO:39 ⁇ SEQ ID NO:30 ⁇ SEQ ID NO:43.
  • the first and third polypeptide chain of DART-A2 comprise, in the N-terminal to C-terminal direction, an N-terminus, a VL domain of a monoclonal antibody capable of binding to PD-L1 (VLPD-L1) (hPD-L1 MAB-2 VL2 (SEQ ID NO:72)), an intervening linker peptide (Linker 1;GGGSGGGG (SEQ ID NO:16)), a VH domain of a monoclonal antibody capable of binding to CD137 (VH CD137 ) (CD137 MAB-6 VH1 (SEQ ID NO:46)), an intervening linker peptide (Linker 2; GGCGGG (SEQ ID NO:18)), a Heterodimer-Promoting (E-coil) Domain (EVAACEK-EVAALEK-EVAALEK-EVAALEK (SEQ ID NO:39)), a linker (LEPKSADKTHTCPPCP (SEQ ID NO:30)), the CH
  • DART-A4 is composed of four polypeptide chains, in which the first and third polypeptide chains are the same and the second and fourth polypeptide chains are the same (see Figure 3B).
  • DART-A4 comprises the binding domains of CD137 MAB-6(1.1) and hPD-L1 MAB-2(3.2).
  • the first and third polypeptide chain of DART-A4 are the same as the first and third polypeptide chain of DART-A2 (SEQ ID NO:120).
  • the second and fourth polypeptide chain of DART-A4 are the same as the second and fourth polypeptide chain of DART-A3 (SEQ ID NO:121).
  • Such alternative DART-A9 first/third polypeptide chains sometimes are composed of: SEQ ID NO:72 ⁇ SEQ ID NO:16 ⁇ SEQ ID NO:46 ⁇ SEQ ID NO:18 ⁇ SEQ ID NO:37 ⁇ SEQ ID NO:30 ⁇ SEQ ID NO:43, and such alternative DART-A9 second/fourth chains sometimes are composed of: SEQ ID NO:50 ⁇ SEQ ID NO:16 ⁇ SEQ ID NO:71 ⁇ SEQ ID NO:18 ⁇ SEQ ID NO:38.
  • DART-A10 DART-A10 is a tetravalent CD137 x CD137 x TA x TA Binding Molecule having two CD137 binding sites and two binding sites for the representative TA, PD-L1.
  • the first polypeptide chain of TRIDENT-A6 comprises, in the N-terminal to C- terminal direction, an N-terminus, a VL domain of a monoclonal antibody capable of binding CD137 (VL CD137 ) (CD137 MAB-6 VL3 (SEQ ID NO:56)), an intervening linker peptide (Linker 1; GGGSGGGG (SEQ ID NO:16)), a VH domain of a monoclonal antibody capable of binding CD137 (VH CD137 ) (CD137 MAB-6 VH1 (SEQ ID NO:46)), an intervening linker peptide (Linker 2; GGCGGG (SEQ ID NO:18)), a Heterodimer-Promoting (E-coil) Domain (EVAALEK-EVAALEK-EVAALEK (SEQ ID NO:37)), an intervening linker peptide (GGGDKTHTCPPCP (SEQ ID NO:21)), a “knob-bearing” CH
  • composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers containing a CD137 x TA Binding Molecule of the present invention alone or with other agents, for example, with a pharmaceutically acceptable carrier. Additionally, one or more other prophylactic or therapeutic agents useful for the treatment of a disease can also be included in the pharmaceutical pack or kit.
  • E49. The PD-L1 Binding Molecule of any one E46-E48, wherein said molecule is an antibody or an antigen binding fragment thereof.
  • E50. The PD-L1 Binding Molecule of any one E46-E48, wherein said molecule is a multispecific binding molecule.
  • the T cell cytokine release assays (using suboptimal stimulated primary T cells in the absence of target cells) were performed essentially as follows: 50 ⁇ L of serially diluted test article (antibodies (+/- cross-linking with anti-human Fc (Fab)’ 2 )), 50 ⁇ L of prewashed Dynabeads ⁇ CD3 (REF 11151D; Invitrogen by Thermo Fisher Scientific, or similar) at 2 x 10 6 beads/mL, and 100 ⁇ L/well of human pan T cells (purified from donor PBMC using Dynabeads Untouched Human T Cells Kit (Invitrogen Cat# 11344D) or similar, per manufacture’s protocol) at 10 6 cells/mL were added to each well of the assay plate.
  • each well on the plate was 200 ⁇ L.
  • assay media was added to bring up the total volume to 200 ⁇ L and the plates were incubated for 72 hours in a tissue culture incubator.
  • FACS analysis to evaluate the test articles for binding to cell surface PD-L1 was performed essentially as follows: 100 ⁇ L of CHO cells expressing PD-L1 (CHO/PD-L1) (1.0 x 10 5 to 1.0 x 10 6 cells/well) and 100 ⁇ L of serially diluted test article was added to each well of microtiter assay plate(s), mixed and incubated at RT for about 30 min. The cells were washed with FACS Buffer and secondary antibody (goat anti-human-FITC, PE, or APC) was then added to each well, after which, the components were mixed and the wells were incubated at RT for about 30 min.
  • FACS Buffer and secondary antibody goat anti-human-FITC, PE, or APC
  • the final volume of each well on the plate was 200 ⁇ L.
  • assay media was added to bring up the total volume to 200 ⁇ L and the plates were incubated for 72 hours in a tissue culture incubator.
  • the supernatants were then collected from each well and the released cytokines of IFN- ⁇ and IL-2 were measured using a Cytokine ELISA Kit (e.g., R&D System (Human IL-2 DuoSet ELISA (Cat: DY202), Human IFN- gamma DuoSet ELISA (Cat: DY285) or similar commercial regents) according to the manufacturer’s instructions.
  • a Cytokine ELISA Kit e.g., R&D System (Human IL-2 DuoSet ELISA (Cat: DY202), Human IFN- gamma DuoSet ELISA (Cat: DY285) or similar commercial regents) according to the manufacturer’s instructions.
  • CD137 x TA Binding Molecules capable of binding to CD137 and to the representative TA, HER2 were generated incorporating the VH and VL Domains of CD137 MAB-6(1.1) and the VH and VL Domains of hHER2 MAB-1(1.3). In this study a number of additional bispecific configurations were examined.

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