US20230272110A1 - Antibodies that bind psma and gamma-delta t cell receptors - Google Patents

Antibodies that bind psma and gamma-delta t cell receptors Download PDF

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US20230272110A1
US20230272110A1 US18/014,457 US202118014457A US2023272110A1 US 20230272110 A1 US20230272110 A1 US 20230272110A1 US 202118014457 A US202118014457 A US 202118014457A US 2023272110 A1 US2023272110 A1 US 2023272110A1
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multispecific antibody
seq
set forth
sequence set
antigen
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Robertus Cornelis ROOVERS
Johannes Jelle VAN DER VLIET
Lisa Anna KING
Paul Willem Henri Ida Parren
Victoria IGLESIAS GUIMARAIS
David Lutje Hulsik
Peter Alexander Gerardus Maria MACHIELSEN
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Lava Therapeutics NV
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Lava Therapeutics NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
    • A61K39/001195—Prostate specific membrane antigen [PSMA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/526—CH3 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Definitions

  • Prostate cancer is the most common cancer in men in Europe and the United States. Early detection of localized disease results in high survival rates. However, metastasized tumors lead to dramatically reduced survival.
  • Prostate-specific membrane antigen also known as folate hydrolase I or glutamate carboxypeptidase II, is a potential target for drug development.
  • PSMA is a type II transmembrane protein showing overexpression on prostatic cancer cells, but low expression in normal tissues.
  • the present invention provides novel antibodies for PSMA-based therapy.
  • Bispecific antibodies were constructed in which PSMA-binding regions were combined with binding regions capable of binding a V ⁇ 9V ⁇ 2 T cell receptor and thus engaging ⁇ T cells.
  • the bispecific antibodies were able to mediate activation of autologous V ⁇ 9V ⁇ 2 T cells, including tumor-infiltrating V ⁇ 9V ⁇ 2 T cells, and to induce killing of patient-derived tumor cells in the presence of autologous PBMC-derived V ⁇ 9V ⁇ 2 T cells with very high potency.
  • ⁇ T cell effector cell
  • target cell tumor cell
  • ⁇ T cell ratios which is important, because ⁇ T cells are only a subpopulation of T cells in humans which can vary in numbers.
  • Normal healthy tissue on the other hand, was not affected, indicating the potential of these antibodies for an efficacious yet safe cancer treatment.
  • studies with whole human blood indicate that in spite of the high potency on target cells, the antibody only induced low levels of cytokine release, suggesting a low risk of cytokine release syndrome.
  • FIG. 8 Cytotoxicity (24-hour assay) of prostate tumor cells induced by V ⁇ 9V ⁇ 2T cells and LV1044-5C8 (“LAVA compound”). *** p ⁇ 0.05. The number of tumor cells (upper panel) or normal cells (lower panel) without treatment was put at 100%.
  • human V ⁇ 9 when used herein, refers to the TRGV9 protein, T cell receptor gamma variable 9 (UniProtKB-Q99603_HUMAN gives an example of a V ⁇ 9 sequence).
  • the antigen-binding region (or antigen-binding domain) which interacts with an antigen may comprise variable regions of both the heavy and light chains of the immunoglobulin molecule or may be a single-domain antigen-binding region, e.g. a heavy chain variable region only.
  • the constant regions of an antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells and T cells) and components of the complement system such as C1q, the first component in the classical pathway of complement activation.
  • antibody as used herein, unless otherwise stated or clearly contradicted by context, includes fragments of an antibody that retain the ability to specifically bind to the antigen. It has been shown that the antigen-binding function of an antibody may be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antibody” include (i) a Fab′ or Fab fragment, i.e. a monovalent fragment consisting of the VL, VH, CL and CH1 domains, or a monovalent antibody as described in WO2007059782; (ii) F(ab′)2 fragments, i.e.
  • the first antigen-binding region or the antigen-binding region, or both is a single domain antibody.
  • Single domain antibodies sdAb, also called Nanobody®, or VHH
  • Single domain antibodies are well known to the skilled person, see e.g. Hamers-Casterman et al. (1993) Nature 363:446, Roovers et al. (2007) Curr Opin Mol Ther 9:327 and Krah et al. (2016) Immunopharmacol Immunotoxicol 38:21.
  • Single domain antibodies comprise a single CDR1, a single CDR2 and a single CDR3.
  • T366W means that the variant comprises a substitution of threonine with tryptophan in the variant amino acid position corresponding to the amino acid in position 366 in the parent antibody.
  • bispecific antibody refers to an antibody having specificities for two different, typically non-overlapping, epitopes. Such epitopes may be on the same or different targets. If the epitopes are on different targets, such targets may be on the same cell or different cells or cell types.
  • IgG-like dual targeting molecules examples include but are not limited to Dual Targeting (DT)-Ig (GSK/Domantis, WO2009058383), Two-in-one Antibody (Genentech, Bostrom, et al 2009. Science 323, 1610-1614), Cross-linked Mabs (Karmanos Cancer Center), mAb2 (F-Star), ZybodiesTM (Zyngenia, LaFleur et al. MAbs. 2013 March-April; 5(2):208-18), approaches with common light chain, KABodies (NovImmune, WO2012023053) and CovX-body® (CovX/Pfizer, Doppalapudi, V. R., et al 2007. Bioorg. Med. Chem. Lett. 17,501-506).
  • DT Dual Targeting
  • GSK/Domantis WO200905838383
  • Two-in-one Antibody Genentech, Bostrom, et al 2009. Science 323, 1610-1614
  • Cross-linked Mabs
  • IgG fusion molecules include but are not limited to Dual Variable Domain (DVD)-Ig (Abbott), Dual domain double head antibodies (Unilever; Sanofi Aventis), IgG-like Bispecific (ImClone/Eli Lilly, Lewis et al. Nat Biotechnol. 2014 February; 32(2):191-8), Ts2Ab (MedImmune/AZ, Dimasi et al. J Mol Biol. 2009 Oct.
  • DVD Dual Variable Domain
  • Abbott Dual domain double head antibodies
  • IgG-like Bispecific ImClone/Eli Lilly, Lewis et al. Nat Biotechnol. 2014 February; 32(2):191-8
  • Ts2Ab MedImmune/AZ, Dimasi et al. J Mol Biol. 2009 Oct.
  • Fab fusion bispecific antibodies include but are not limited to F(ab)2 (Medarex/AMGEN), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock® (DNL) (ImmunoMedics), Bivalent Bispecific (Biotecnol) and Fab-Fv (UCB-Celltech).
  • ScFv-, diabody-based and domain antibodies include but are not limited to Bispecific T Cell Engager (BiTE®) (Micromet, Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DARTTM) (MacroGenics), Single-chain Diabody (Academic, Lawrence FEBS Lett. 1998 Apr. 3; 425(3):479-84), TCR-like Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack, WO2010059315) and COMBODY molecules (Epigen Biotech, Zhu et al. Immunol Cell Biol. 2010 August; 88(6):667-75), dual targeting Nanobodies® (Ablynx, Hmila et al., FASEB J. 2010), dual targeting heavy chain only domain antibodies.
  • BiTE® Bispecific T Cell Engager
  • DARTTM Dual Affinity Retargeting Technology
  • Single-chain Diabody Academic,
  • the antibody is capable of inducing killing of LNCaP, 22Rv1 or VCaP cells through activation of V ⁇ 9V ⁇ 2 T cells with an EC50 value of 50 pM or less, such as 25 pM or less, e.g. 20 pM or less, such as 15 pM or less when tested after 24 hours as described in Example 13 herein, preferably both at a 1:1 and a 1:10 effector to target cell ratio.
  • the multispecific antibody of the invention is capable of binding to the PSMA positive prostate cancer cell line LNCaP with an EC50 of 50 nM or less, such as 20 nM or less, e.g. 10 nM of less, when tested as described in Example 7 herein.
  • the multispecific antibody of the invention is capable of binding to V ⁇ 9V ⁇ 2 T cells with an EC50 of 10 nM or less, such as 5 nM or less, e.g. 2 nM of less, when tested as described in Example 7 herein.
  • the multispecific antibody is capable of mediating killing of human PSMA-expressing cells from a prostate cancer patient. Killing of human PSMA-expressing cells from a prostate cancer patient may e.g. be determined as described in Example 10 herein. In one embodiment, the multispecific antibody of the invention is capable of mediating specific cell death of more than 25%, such as more than 50%, at a concentration of 50 nM, as determined in the assays described in Example 10 or Example 14 herein.
  • the multispecific antibody further comprises a half-life extension domain.
  • the multispecific antibody has a terminal half-life that is longer than about 168 hours when administered to a human subject. Most preferably the terminal half-life is 336 hours or longer.
  • the “terminal half-life” of an antibody when used herein refers to the time taken for the serum concentration of the polypeptide to be reduced by 50%, in vivo in the final phase of elimination.
  • the CH3 regions of the Fc polypeptides comprise said asymmetric amino acid mutations, preferably the first Fc polypeptide comprises a T366W substitution and the second Fc polypeptide comprises T366S, L368A and Y407V substitutions, or vice versa, wherein the amino acid positions correspond to human IgG1 according to the EU numbering system.
  • cysteine residues at position 220 in the first and second Fc polypeptides have been deleted or substituted, wherein the amino acid position corresponds to human IgG1 according to the EU numbering system.
  • the region comprises the sequence set forth in SEQ ID NO:10.
  • the first antigen-binding region comprises the sequence set forth in SEQ ID NO:2
  • the second antigen-binding region comprises the sequence set forth in SEQ ID NO:5 and
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a multispecific antibody according to the invention as described herein and a pharmaceutically-acceptable excipient.
  • Antibodies may be formulated with pharmaceutically-acceptable excipients in accordance with conventional techniques such as those disclosed in (Rowe et al., Handbook of Pharmaceutical Excipients, 2012 June, ISBN 9780857110275).
  • the pharmaceutically-acceptable excipient as well as any other carriers, diluents or adjuvants should be suitable for the antibodies and the chosen mode of administration.
  • Suitability for excipients and other components of pharmaceutical compositions is determined based on the lack of significant negative impact on the desired biological properties of the chosen antibody or pharmaceutical composition of the present invention (e.g., less than a substantial impact (10% or less relative inhibition, 5% or less relative inhibition, etc.) upon antigen binding).
  • the pharmaceutical composition comprises a multispecific antibody of the invention (preferably an antibody comprising an Fc region), a buffer and an antioxidant, wherein the pH of the composition is between 5.4 and 7.4, such as between 5.4 and 6.1.
  • the pharmaceutical composition comprises a multispecific antibody of the invention comprising an Fc region, a histidine or sodium acetate buffer, sucrose, polysorbate 80 and methionine, wherein the pH of the composition is between 5.4 and 7.4, such as between 5.4 and 6.1.
  • the invention relates to the multispecific antibody according to the invention as described herein for use as a medicament.
  • the antibody is administered as monotherapy.
  • antibodies of the present invention may also be administered in combination therapy, i.e., combined with other therapeutic agents relevant for the disease or condition to be treated.
  • Multispecific antibodies of the invention are typically produced recombinantly, i.e. by expression of nucleic acid constructs encoding the antibodies in suitable host cells, followed by purification of the produced recombinant antibody from the cell culture.
  • Nucleic acid constructs can be produced by standard molecular biological techniques well-known in the art. The constructs are typically introduced into the host cell using an expression vector. Suitable nucleic acid constructs and expression vectors are known in the art.
  • Host cells suitable for the recombinant expression of antibodies are well-known in the art, and include CHO, HEK-293, Expi293F, PER-C6, NS/0 and Sp2/0 cells.
  • the invention relates to an expression vector comprising a nucleic acid construct encoding a multispecific antibody according to the invention.
  • PBMC peripheral blood mononuclear cells
  • V ⁇ 9V ⁇ 2-T cells were stimulated every seven days with a feeder cell mix consisting of irradiated PBMC from two healthy donors and an Epstein Barr Virus transformed B cell line (JY) resuspended in Roswell Park Memorial Institute (RPMI) medium supplemented with 10 IU/mL IL-7, 10 ng/mL IL-15 and 50 ng/ml PHA. Expanded V ⁇ 9V ⁇ 2-T cell cultures were always tested for purity before being used for experiments and always found to be >95% V ⁇ 9 and V ⁇ 2 double positive.
  • JY Epstein Barr Virus transformed B cell line
  • RPMI Roswell Park Memorial Institute
  • a concentration range of antibody was tested for binding to the PSMA positive prostate cancer cell line LNCaP and to the antigen negative cell line PC-3. Detection was performed with a polyclonal anti-human IgG antibody.
  • V ⁇ 9V ⁇ 2-T cells were not activated by LV1050-Fc x 5C8var1-Fc alone (in the absence of tumor cells), neither was lysis observed of tumor cells in which PSMA expression was abrogated (LNCaP.koPSMA)( FIG. 11 A ).
  • TGI tumor growth inhibition
  • LV1050-Fc x 5C8var1-Fc only induced the release of IL-8 and IFN- ⁇ .
  • the LV1050-Fc x 5C8var1-Fc-induced release of IL-8 was comparable to that induced by Erbitux®, an antibody that is known not to induce cytokine release syndrome (CRS) (or is known to induce low levels of cytokines) in patients.
  • LV1050-Fc x 5C8var1-Fc induced an IFN- ⁇ release that was slightly higher when compared to Erbitux®, but the highest IFN- ⁇ release observed was much lower than that induced by Campath®, an antibody clinically associated with CRS.
  • LV1050-Fc x 5C8var1-Fc did not induce any IL-6 release, a prominent cytokine in CRS (Tanaka et al (2016) Immunotherapy 8: 959).
  • LV1050-Fc x 5C8var1-Fc In an in vitro cytokine release assay where LV1050-Fc x 5C8var1-Fc was coated to high-binding 96 wells plates prior to incubation with fresh whole blood from 10 healthy donors, similar results were obtained.
  • LV1050-Fc x 5C8var1-Fc induced very low (median) levels of IL-6 and IL-8, which were comparable to the low response comparator, Erbitux® and no TNF ⁇ release was observed.
  • LV1050-Fc x 5C8var1-Fc induced higher (median) levels of IFN ⁇ compared with Erbitux® at each concentration of the compound tested, yet median levels were substantially lower than that induced by Campath®.
  • LV1050-Fc x 5C8var1-Fc The pharmacokinetics of LV1050-Fc x 5C8var1-Fc were also evaluated in non-human primates (NHP). Three female cynomolgus monkeys were given a single IV dose of LV1050-Fc x 5C8var1-Fc (0.14, 0.77 and 2.27 mg/kg (1 animal per dose)) using a 30-minute IV infusion. The half-life of LV1050-Fc x 5C8var1-Fc ranged between 150 and 166 hours (6.3-6.9 days) ( FIG. 17 ), which is in line with the half-lives of IgG-based humanized antibodies which do not bind to the cynomolgus ortholog targets (Walker et al. (2019) PLOS ONE 14: e0217061). A dose-proportional increase in exposure was observed. The pharmacokinetic parameters are provided in Table 6.
  • SE-HPLC Size Exclusion High Performance Liquid Chromatography
  • Formulated samples were subjected to several storage conditions (defined below), for up to 12 weeks. Additionally, several stress tests were applied:
  • LV1050-Fc x 5C8var1-Fc was most stable when formulated in buffer 2 and buffer 4.
  • An overview of the sum of results outside their predefined analytical threshold for temperature stability, stress stability and overall stability (temperature plus stress) is shown in Table 8.

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US12428493B2 (en) 2020-07-08 2025-09-30 LAVA Therapeutics N.V. Antibodies that bind PSMA and gamma-delta T cell receptors

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EP4292609A1 (en) * 2022-06-15 2023-12-20 LAVA Therapeutics N.V. Compositions comprising antibodies that bind gamma-delta t cell receptors
EP4292610A1 (en) * 2022-06-15 2023-12-20 LAVA Therapeutics N.V. Variant antibodies that bind gamma-delta t cell receptors
JP2025519645A (ja) * 2022-06-23 2025-06-26 ラヴァ・セラピューティクス・エヌ・ヴイ Ｔ細胞依存性多重特異性化合物のアッセイ
CN121426967A (zh) * 2023-02-10 2026-01-30 阿穆尼克斯制药公司 靶向前列腺特异性膜抗原（psma）的组合物及其制备和使用方法
EP4438624A1 (en) * 2023-03-27 2024-10-02 LAVA Therapeutics N.V. Antibodies that bind nectin-4 and gamma-delta t cell receptors
WO2024200573A1 (en) 2023-03-27 2024-10-03 LAVA Therapeutics N.V. Nectin-4 binding agents and methods of use
WO2025012118A2 (en) 2023-07-07 2025-01-16 LAVA Therapeutics N.V. 5t4 binding agents and methods of use

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