WO2018148445A1 - Multi-specific binding proteins for activation of natural killer cells and therapeutic uses thereof to treat cancer - Google Patents

Multi-specific binding proteins for activation of natural killer cells and therapeutic uses thereof to treat cancer Download PDF

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Publication number
WO2018148445A1
WO2018148445A1 PCT/US2018/017470 US2018017470W WO2018148445A1 WO 2018148445 A1 WO2018148445 A1 WO 2018148445A1 US 2018017470 W US2018017470 W US 2018017470W WO 2018148445 A1 WO2018148445 A1 WO 2018148445A1
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Prior art keywords
cells
cancer
antigen
tumor
nkg2d
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PCT/US2018/017470
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English (en)
French (fr)
Inventor
Gregory P. CHANG
Ann F. CHEUNG
William Haney
Asya Grinberg
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Adimab LLC
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Adimab LLC
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Priority to US16/483,330 priority Critical patent/US11834506B2/en
Priority to IL268554A priority patent/IL268554B2/en
Priority to BR112019016315-8A priority patent/BR112019016315B1/pt
Priority to FIEP18751476.5T priority patent/FI3579848T3/fi
Priority to EP24202255.6A priority patent/EP4491234A3/en
Priority to RS20250083A priority patent/RS66445B1/sr
Priority to SG11201907299XA priority patent/SG11201907299XA/en
Priority to DK18751476.5T priority patent/DK3579848T3/da
Priority to KR1020247004661A priority patent/KR20240023449A/ko
Priority to KR1020257018720A priority patent/KR20250089564A/ko
Priority to CN201880023211.3A priority patent/CN110944651A/zh
Priority to KR1020197026247A priority patent/KR20190118172A/ko
Priority to MX2019009468A priority patent/MX2019009468A/es
Priority to JP2019563733A priority patent/JP2020506971A/ja
Priority to CA3053010A priority patent/CA3053010A1/en
Priority to AU2018219887A priority patent/AU2018219887B2/en
Priority to EP18751476.5A priority patent/EP3579848B1/en
Priority to RU2019128060A priority patent/RU2809125C2/ru
Priority to ES18751476T priority patent/ES3005783T3/es
Application filed by Adimab LLC filed Critical Adimab LLC
Publication of WO2018148445A1 publication Critical patent/WO2018148445A1/en
Anticipated expiration legal-status Critical
Priority to JP2022077006A priority patent/JP2022101709A/ja
Priority to US18/482,629 priority patent/US20240166753A1/en
Priority to JP2024077012A priority patent/JP2024099850A/ja
Ceased legal-status Critical Current

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Definitions

  • FIG. 6 is a representation of a TriNKET in the Orthogonal Fab interface (Ortho- Fab) form, which is an heterodimeric construct that contains 2 Fabs binding to target 1 and target 2 fused to Fc. LC-HC pairing is ensured by orthogonal interface. Heterodimerization is ensured by mutations in the F c .
  • FIG. 31 is a graph showing multi-specific binding proteins induced higher levels of cytotoxicity towards tumor target cells by human NK cells.
  • FIG. 35 is a graph showing multi-specific binding proteins induced higher levels of cytotoxicity towards tumor target cells by mouse NK cells.
  • tumor associated antigen means any antigen including but not limited to a protein, glycoprotein, ganglioside, carbohydrate, lipid that is associated with cancer. Such antigen can be expressed on malignant cells or in the tumor
  • salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W
  • An alternative format of the heterodimeric multi- specific proteins includes a first immunoglobulin heavy chain, a second immunoglobulin heavy chain, a first immunoglobulin light chain and a second immunoglobulin light chain.
  • the first immunoglobulin heavy chain includes a first Fc (hinge-CH2-CH3) domain, a first variable heavy chain domain and an optional first CHI heavy chain domain.
  • the first immunoglobulin light chain includes a variable light chain domain and a constant light chain domain. Together with the first immunoglobulin heavy chain, the first immunoglobulin light chain forms an antigen-binding site that binds a tumor antigen.
  • T366S/L368A/Y407VCH3B The "hole" mutation was optimized by structured-guided phage library screening (Atwell S, Ridgway JB, Wells JA, Carter P. Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library. J Mol Biol (1997) 270(l):26-35). X-ray crystal structures of KiH Fc variants (Elliott JM, Ultsch M, Lee J, Tong R, Takeda K, Spiess C, et al. , Antiparallel conformation of knob and hole aglycosylated half-antibody homodimers is mediated by a CH2-CH3 hydrophobic interaction.
  • TriNKETs described herein which include an NKG2D- binding domain and a binding domain for a tumor associated antigen, bind to cells expressing human NKG2D.
  • TriNKETs which include an NKG2D-binding domain and a binding domain for a tumor associated antigen, bind to the tumor associated antigen at a comparable level to that of a monoclonal antibody having the same tumor associated antigen-binding domain.
  • TriNKETs that include an NKG2D-binding domain and a HER2 -binding domain from Trastuzumab can bind to HER2 expressed on cells at a level comparable to that of Trastuzumab.
  • TriNKETs described herein e.g. , A40-TriNKET, A44-TriNKET, A49-TriNKET, C26-TriNKET, F04-TriNKET, F43-TriNKET, F47-TriNKET, and F63-TriNKET
  • a tumor associated antigen non-limiting examples of tumor associated antigens including
  • TriNKETs described herein including an NKG2D-binding domain e.g. , A40-TriNKET, A44-TriNKET, A49-TriNKET, C26-TriNKET, F04-TriNKET, F43 -TriNKET, F47-TriNKET, and F63 -TriNKET
  • a tumor associated antigen non-limiting examples of tumor associated antigens including CD20, BCMA, and HER2
  • TriNKETs including an NKG2D-binding domain and a tumor antigen-binding domain are more effective against cancer metastases than monoclonal antibodies that include the same tumor antigen-binding domain.
  • the amount of multi-specific binding protein and additional therapeutic agent and the relative timing of administration may be selected in order to achieve a desired combined therapeutic effect.
  • the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • a multi-specific binding protein may be administered during a time when the additional therapeutic agent(s) exerts its prophylactic or therapeutic effect, or vice versa.
  • compositions that contain a therapeutically effective amount of a protein described herein (e.g. , A40-TriNKET, A44-
  • the formulation includes a buffer system which contains citrate and phosphate to maintain the pH in a range of about 4 to about 8.
  • the pH range may be from about 4.5 to about 6.0, or from about pH 4.8 to about 5.5, or in a pH range of about 5.0 to about 5.2.
  • the buffer system includes citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, and/or sodium dihydrogen phosphate dihydrate.
  • the buffer system includes about 1.3 mg/ml of citric acid (e.g. , 1.305 mg/ml), about 0.3 mg/ml of sodium citrate (e.g.
  • the pH of the liquid formulation may be set by addition of a pharmaceutically acceptable acid and/or base.
  • the pH of the liquid formulation may be set by addition of a pharmaceutically acceptable acid and/or base.
  • pharmaceutically acceptable acid may be hydrochloric acid.
  • the base may be sodium hydroxide.
  • the lyoprotectant may be sugar, e.g. , disaccharides.
  • the lycoprotectant may be sucrose or maltose.
  • the lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and/or a preservative.
  • the amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1:2 protein to sucrose or maltose.
  • the protein to sucrose or maltose weight ratio may be of from 1 :2 to 1:5.
  • a “bulking agent” may be added.
  • a “bulking agent” is a compound which adds mass to a lyophilized mixture and contributes to the physical structure of the lyophilized cake (e.g. , facilitates the production of an essentially uniform lyophilized cake which maintains an open pore structure).
  • Illustrative bulking agents include mannitol, glycine, polyethylene glycol and sorbitol. The lyophilized formulations of the present invention may contain such bulking agents.
  • SC2.2 is single chain protein including an scFv derived from trastuzumab, and ULBP-6 (SEQ ID NO:73).
  • AL0.2 showed enhanced lysis of SkBr-3 target cells by human NK cells than trastuzumab in a does dependent manner, with a p value of 0.0311 in EC50 (FIG. 31).
  • the CD20-binding domain used in the tested molecules was composed of a heavy chain variable domain and a light chain variable domain.
  • the BCMA-binding domain used in the tested molecules was composed of a heavy chain variable domain and light chain variable domain as listed below.
  • Example 12 Trispecific-binding proteins enable cytotoxicity of target cancer cells
  • lOx lysis buffer was added to wells containing only cancer cells, and to wells containing only media for the maximum lysis and negative reagent controls, respectively. The plate was then placed back into the incubator for an additional 45 minutes to reach a total of 4 hours incubation. Cells were then pelleted, and the culture supernatant was transferred to a new 96 well plate and mixed with a substrate for development.
  • TriNKETs mediate cytotoxicity of human NK cells against the CD33-positive Molm-13 human AML cell line.
  • rested human NK cells were mixed with Molm- 13 cancer cells, and TriNKETs (e.g. , C26-TriNKET-CD33 and F04-TriNKET- CD33) are able to enhance the cytotoxic activity of rested human NK cells in a dose- responsive manner against the cancer cells.
  • the dotted line indicates cytotoxic activity of rested NK cells without TriNKETs.
  • NK cells The ability of human NK cells to lyse tumor cells was measured with or without the addition of TriNKETs using the cyto Tox 96 non-radioactive cytotoxicity assay from Promega (G1780).
  • Human cancer cell lines expressing a cancer target of interest were harvested from culture, cells were washed with PBS, and were resuspended in growth media at l-2xl0 5 /mL for use as target cells. 50 ⁇ of the target cell suspension were added to each well.
  • Monoclonal antibodies or TriNKETs targeting a cancer antigen of interest were diluted in culture media, 50 ⁇ of diluted mAb or TriNKET were added to each well.
  • NK cells were added to each well of the plate to make a total of 200 ⁇ culture volume. The plate was incubated at 37 °C with 5% C02 for 2-3 hours before developing the assay.
  • NK cells are activated by TriNKETs in co-culture with human cancer lines expressing varying levels of HER2
  • Trastuzumab + bispecific combination demonstrates the importance of containing the trispecific-binding of TriNKETs in one molecule.

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