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BR-122023000741-B1 - Use of humanized anti-IL-1R3 antibodies, fragments or derivatives thereof in the manufacture of a pharmaceutical composition for the treatment of an IL-1R3-mediated disease.

BR122023000741B1BR 122023000741 B1BR122023000741 B1BR 122023000741B1BR-122023000741-B1

Abstract

This disclosure relates to humanized antibodies that bind specifically to IL-1R3 or a fragment or derivative thereof, or a polypeptide containing at least a portion of said antibody sufficient to confer IL-1R3 binding specificity. Said antibodies inhibit IL-1R3-induced NFkB activity. They also inhibit IL-1α, IL-1β, IL-33, and/or IL-36-stimulated NFkB activity. The disclosure further relates to the use of said humanized antibody in the treatment of an IL-1R3-mediated disease, such as cancer. Finally, the disclosure encompasses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody according to the invention. The pharmaceutical composition can be used in the treatment of an IL-1R3-mediated disease, such as cancer.

Inventors

  • Stephan Fischer
  • Michael Brandt
  • LINDA VERONIQUE KAZANDJIAN

Assignees

  • SANOFI BIOTECHNOLOGY

Dates

Publication Date
20260310
Application Date
20170508
Priority Date
20160506

Claims (7)

  1. 1. Use of a humanized antibody that specifically binds to IL-1R3 or antibody fragment or antibody derivative containing at least a portion of said antibody sufficient to confer IL-1R3 binding specificity, wherein the antibody, antibody fragment or antibody derivative comprises three heavy chain CDRs and three light chain CDRs selected from the group consisting of:(1) CDR1H according to SEQ ID NO: 77, CDR2H according to SEQ ID NO: 94, CDR3H according to SEQ ID NO: 111, CDR1L according to SEQ ID NO: 128, CDR2L according to SEQ ID NO: 145 and CDR3L according to SEQ ID NO: 162,(2) CDR1H according to SEQ ID NO: 79, CDR2H according to SEQ ID NO: 96, CDR3H according to SEQ ID NO: 113, CDR1L according to SEQ ID NO: 130, CDR2L according to SEQ ID NO: 147 and CDR3L according to SEQ ID NO: 175, and(3) CDR1H according to SEQ ID NO: 81, CDR2H according to SEQ ID NO: 98, CDR3H according to SEQ ID NO: 115, CDR1L according to SEQ ID NO: 132, CDR2L according to SEQ ID NO: 149 and CDR3L according to SEQ ID NO: 166, characterized in that it is for the manufacture of a pharmaceutical composition for the treatment of an IL-1R3-mediated disease, wherein the IL-1R3-mediated disease is an acute or chronic inflammation, optionally an inflammatory disease selected from the group consisting of arthritis, osteoarthritis and inflammatory skin responses.
  2. 2. Use according to claim 1, characterized in that the antibody comprises a variable heavy chain (VH) region comprising an amino acid sequence selected from the group consisting of (1) a VH region according to SEQ ID NO: 26, (2) a VH region according to SEQ ID NO: 28, and (3) a VH region according to SEQ ID NO: 30.
  3. 3. Use according to claim 2, characterized in that the antibody comprises a variable light chain (VL) region comprising an amino acid sequence selected from the group consisting of (1) a VL region according to SEQ ID NO: 60, (2) a VL region according to SEQ ID NO: 174, and (3) a VL region according to SEQ ID NO: 64.
  4. 4. Use according to any one of claims 1 to 3, characterized in that it inhibits: (i) NFkB activity induced by IL-1R3, (ii) NFkB activity stimulated by IL-1 alpha, IL-1 beta, IL-33 and/or IL-36, and/or (iii) NFkB activity stimulated by a complex selected from the group consisting of IL-1β/IL-1R1/IL-1RAcP, IL-1α/IL-1R1/IL-1RacP, IL-33/ST2/IL-1RAcP and/or IL-36/II-36R/11-1RAcP.
  5. 5. Use according to any of claims 1 to 4, characterized in that said antibody inhibits, at a concentration of 10 μg/mL, the expression of NFkB in lysates of A549-NFkB-RE-Luc cells stimulated with 0.1 ng/mL of human IL-1 alpha, human IL-1 beta, IL-33 and/or IL-36, by 50% or more, preferably by 60% or more, preferably by 70% or more, preferably by 80% or more, preferably by 90% or more, and most preferably by 95% or more, compared to the same assay without said antibody.
  6. 6. Use in accordance with any one of claims 1 to 5, characterized in that said antibody inhibits the activity of luciferase stimulated by IL-1 alpha, IL-1 beta, IL-33 and/or IL-36, respectively, in HE-K293T/17 cells transfected with luciferase under the control of the NF-kB reporter gene.
  7. 7. Use in accordance with any one of claims 1 to 6, characterized in that said antibody comprises at least the amino acid substitutions L234A and L235A in the FC region of human IgG1 or S228P and L235E in the FC region of human IgG4.

Description

Field of Invention [001] The present invention relates to humanized anti-IL-1R3 antibodies and their use. Fundamentals [002] Interleukin-1 receptor accessory protein (IL1RAP), also called IL1R3, is a co-receptor of interleukin-1 receptor type 1 (IL1R1) and is indispensable for IL-1 signaling transmission. After IL-1 binding, IL-1R1 associates with IL-1RAcP forming a functional signaling receptor complex, which stimulates NFkB activity. [003] IL-33, its ST2 receptor, and IL-1RAcP also form a complex (IL-33/ST2/IL-1RAcP) with similar activity regarding NFkB activation as the IL-1β/IL-1R1/IL-1RAcP complex. IL-36 (IL-36α (IL-16F), IL-36β (IL-1F8), and IL-36Y (IL-1F9)), its IL-36R receptor, and IL-1RAcP also form a complex (IL-36/IL-36R/IL-1RAcP) with similar activity regarding NFkB activation as the IL-1β/IL-1R1/IL-1RAcP complex. [004] Human NF-κB is an important regulator of the expression of several genes involved in inflammation, immune response, and apoptosis. Therefore, NFκB dysfunction is involved in the pathology of several diseases, including autoimmune diseases, neurodegenerative diseases, inflammation, and cancers. For example, in the treatment of osteoarthritis (OA), the NF-κB pathway is an important target. Thus, agents that regulate the human NFκB pathway by inhibiting the signaling activity of the human IL-1RL/IL-1RAcP complex represent potential treatments for various human diseases. In particular, high-affinity neutralizing antibodies would be excellent therapeutic agents. [005] For over 15 years, attempts have been made to generate functional monoclonal antibodies against human IL-1RAcP. However, many attempts have failed, and existing antibodies still present several drawbacks. WO199623067 refers to an IL-1RAcP antibody that specifically binds to the murine IL-1 receptor accessory protein. Examples 15 and 16 describe attempts to generate anti-human IL-1RAcP antibodies that neutralize the biological activity of IL-1. However, this antibody is not provided by WO199623067, and Example 16, which describes an IL-1-induced IL-6 assay, is only hypothetical. Do-Young Yoon D-Y and Charles A. Dinarello CA describe this in J. Immunol. 1998; 160:3170-3179 Polyclonal antibodies to domains II and III of murine IL-1RAcP that inhibit IL-1beta activity but do not bind. However, at higher concentrations of IL-1beta (1000 pg/mL), this polyclonal antiserum does not block D10S cell proliferation. (D10S is a subclone of the murine D10.G4.1 helper T cell that proliferates at subfemtomolar (attomolar) concentrations of IL-1 beta or alpha in the absence of mitogens, cf. Orencole SF and Dinarello CA; Cytokine 1 (1989) 14-22). Jaras M. et al., PNAS 107 (2010) 16280-16285 describes the use of polyclonal anti-IL1RAcP rabbit KMT-1 antibodies to kill CML stem cells. This antibody induces ADCC in an IL1RAcP-independent manner caused by its rabbit Fc portion. Jaras et al. expect that "potential future therapeutic IL1RAP-targeting antibodies will show low toxicity in normal hematopoietic cells". Polyclonal rabbit antibodies against murine IL-1RAcP were also mentioned in Do-Young Yoon and Charles A. Dinarello, Journal of Biochemistry and Molecular Biology, Vol. 40, No. 4, July 2007, pp. 562-570. [006] WO2002064630 also refers to IL-1RAcP and its use, but no antibody against IL-1RAcP is described. WO2004022718 and WO2009120903 theoretically mention that antibodies against CSF1R, IL13RA1, IL1RAP, IFNAR1, IL5R, INSR, IL1RL1, LTK, and TACSTD1 could be generated according to the state of the art. However, here too, no antibody against IL-1RAcP is described. WO2011021014 and WO2012098407 (US20140017167) refer to polyclonal rabbit anti-human IL-1RAcP antiserum KMT-1 (see Jaras et al. 2010) and its use. WO2014100772 refers to an anti-IL-1RAcP antibody that binds to IL-1RAcP. However, no activity with respect to the inhibition of any functional signaling receptor complex (such as IL-1β/IL-1R1/IL-1RAcP) that stimulates NFkB activity is described. US6280955 refers to IL-1RAcP and its use, but again no antibody against IL-1RAcP is described. [007] WO2004100987 refers to the use of an interleukin-1 (IL-1) antagonist in the preparation of a drug for the treatment of neointimal hyperplasia and the use of an IL-1 antagonist for the treatment of neointimal hyperplasia. As an antagonist, an anti-IL-1RAcP antibody is suggested, but not further described. US2003 026806 refers to antibodies that bind to IL-1. WO2002064630 also refers to an IL-1 antagonist and the IL-1RAcP protein. Although the use of IL-1RAcP for screening IL-1RAcP antagonists is mentioned, such a method or antagonist is not disclosed. [008] This shows that it has been extremely difficult to identify monoclonal antibodies with high affinity, high specificity and potent neutralizing activity against IL-1R3. The present invention encompasses a humanized IL-1R3 antibody, with high affinity and specificity for IL-1R3, with potent IL-1R3 neutralizing activity, and improved stability. Su