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EP1536825A1 - Hybride d'interferon et de fragment fc d'immunoglobuline - Google Patents

Hybride d'interferon et de fragment fc d'immunoglobuline

Info

Publication number
EP1536825A1
EP1536825A1 EP02753441A EP02753441A EP1536825A1 EP 1536825 A1 EP1536825 A1 EP 1536825A1 EP 02753441 A EP02753441 A EP 02753441A EP 02753441 A EP02753441 A EP 02753441A EP 1536825 A1 EP1536825 A1 EP 1536825A1
Authority
EP
European Patent Office
Prior art keywords
interferon
protein
fragment
hybrid
terminal end
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02753441A
Other languages
German (de)
English (en)
Other versions
EP1536825A4 (fr
Inventor
Tse Wen Chang
Liming Yu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genentech Inc
Original Assignee
Tanox Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tanox Inc filed Critical Tanox Inc
Priority claimed from PCT/US2002/025154 external-priority patent/WO2004022088A1/fr
Publication of EP1536825A1 publication Critical patent/EP1536825A1/fr
Publication of EP1536825A4 publication Critical patent/EP1536825A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]

Definitions

  • This invention relates to protein hybrids having an interferon protein covalently linked to an immunoglobulin Fc fragment, including hybrids having peptide linkers linking the interferon protein and immunoglobulin Fc fragment.
  • Interferons including interferon- ⁇ ("IFN ⁇ ”) and interferon- ⁇ ('TFN ⁇ ”), were among the first cytokines to be produced by recombinant DNA technology.
  • IFN ⁇ has been shown to have therapeutic value in conditions such as hairy cell leukemia and inflammatory and viral diseases, including hepatitis B. IFN ⁇ has been approved for use in treatment of multiple sclerosis.
  • IFN ⁇ cytokines
  • cytokines including IFN ⁇
  • IFN ⁇ have relatively short circulation half-lives because they are produced in vivo to act locally and transiently.
  • To use IFN ⁇ as an effective systemic therapeutic relatively large doses and frequent administrations are needed. Such frequent administrations are inconvenient and painful. Further, the toxic side effects associated with IFN ⁇ administration are so severe that some cancer patients cannot tolerate the treatment. These side effects are probably associated with administration of a high dosage.
  • the molecule can be modified to increase its circulation half-life or the molecule's formulation can be modified to extend its release time. The dosage and administration frequency can then be reduced to increase the efficacy.
  • Efforts have been made to create a recombinant IFN ⁇ -gelatin hybrid with an extended retention time (Tabata, Y. et al., Cancer Res. 51:5532-8, 1991).
  • a lipid-based encapsulated IFN ⁇ formulation has also been tested in animals and achieved an extended release of the protein in the peritoneum (Bonetti, A. and Kim, S. Cancer Chemother Pharmacol. 33:258-261, 1993).
  • IgG and IgM immunoglobulins are among the most abundant proteins in the human blood. They circulate with half-lives ranging from several days to 21 days. IgG has been found to increase the half-lives of several ligand binding proteins (receptors) when used to form recombinant hybrids, including the soluble CD4 molecule, LHR, and the IFN- ⁇ receptor (Mordenti J. et al, Nature, 337:525-31, 1989; Capon, D.J. and Lasky, L.A., U.S. Patent number 5,116,964; Kurschner, C. et al, J. Immunol. 149:4096-4100, 1992).
  • ligand binding proteins receptors
  • an immunoglobulin Fc joined by a peptide linker disclose hybrid recombinant proteins consisting of human interferon and a human immunoglobulin Fc fragment joined by a peptide linker comprising the sequence Gly Gly Ser Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser.
  • a protein hybrid comprising an interferon protein covalently linked at its C-terminal end to the N-terminal end of an immunoglobulin Fc fragment or a protein hybrid comprising an interferon protein covalently linked at its C- terminal end to the N-terminal end of a peptide linker that is covalently linked at its C- terminal end to the N-terminal end of an immunoglobulin Fc fragment.
  • the preferred linker is an immunologically inert peptide consisting of Gly Ser repeat unit having from about 2 to about 40 amino acids.
  • the linkers may also be T cell inert amino acid sequences or any non- immunogenic amino acid sequence.
  • the hybrids of the present invention are useful for treating patients with tumors to remove tumors, regress tumors, or delay tumor development.
  • SEQ ID NO:l is the nucleotide and amino acid sequence of an JJFN- ⁇ -Fc hybrid.
  • SEQ ED NO:2 is the amino acid sequence of an IFN- ⁇ -Fc hybrid shown in SEQ ID NO:
  • SEQ ED NOS:3-9 are the amino acid sequences of the various length peptide linkers used to conjugate the N-terminal end(s) of a heavy chain ⁇ 4 Fc fragment to the C-terminal end of an IFN- ⁇ protein.
  • SEQ ID NO: 10 is the amino acid sequence of a linker used to conjugate the N-terminal end of a heavy chain ⁇ l Fc fragment to the C-terminal end of an IFN- ⁇ protein as used in an assay as described below.
  • SEQ ID NO:l 1 is the amino acid sequence of a linker used to conjugate the N-terminal end of a heavy chain ⁇ 4 Fc fragment to the C-terminal end of an IFN- ⁇ protein which molecule was then used in an in vitro cytopathic effect assay as described below.
  • Fig. 1 shows a virus cytopathic effect inhibition assay for various linkers in an IFN- ⁇ -Fc hybrid.
  • Fig. 2 shows a virus cytopathic effect inhibition assay for two different linkers in an IFN- ⁇ -Fc hybrid.
  • the present invention provides a protein hybrid comprising an interferon protein covalently linked at its C-terminal end to the N-terminal end of an immunoglobulin Fc fragment.
  • the interferon protein can be any Type I interferon including interferon- ⁇ , interferon- ⁇ , interferon- ⁇ , interferon- ⁇ , and interferon- ⁇ or Type II interferon including interferon- ⁇ .
  • the interferon protein in an interferon- ⁇ or interferon- ⁇ , most preferably an interferon- ⁇ 2a or interferon- ⁇ 2b.
  • the immunoglobulin Fc fragment can be a fragment from any class of immunoglobin including IgA, IgD, IgE, IgG, or IgM.
  • the Fc fragment is a human immunoglobulin Fc fragment, most preferably an IgG Fc fragment of the IgG4( ⁇ 4) subclass.
  • the ⁇ 4 chain is preferred over the ⁇ l chain because the former demonstrates little or no antibody-dependant cell-mediated cytotoxicity (ADCC) or complement activating ability and is stable in human circulation.
  • the present invention also provides a protein hybrid homodimer comprising two interferon proteins covalently linked at their C-terminal end to each of the two N-terminal ends of an immunoglobulin Fc fragment, preferably a ⁇ 4 Fc fragment.
  • the present invention also provides a protein hybrid comprising an interferon protein covalently linked at its C-terminal end to the N-terminal end of a peptide linker that is covalently linked at its C-terminal end to the N-terminal end of an immunoglobulin Fc fragment.
  • the interferon protein and Fc fragments are linked through a T cell immunologically inert peptide, preferably peptides with Gly Ser repeat units. Because these peptides are immunologically inactive, their insertion at the fusion point eliminates any neoantigenicity that may develop when directly joining of the interferon and Fc fragment.
  • the peptide linker is preferably an immunologically inert peptide consisting of Gly Ser repeat unit having from about 2 to about 40 amino acids. Typical amino acid sequences for the peptide linker are shown in SEQ ID NOS 3, 4, 5, 6, 7, 8, and 9. These linkers have the unique ability to connect interferons and Fc fragments without significantly adversely affecting the biological activity of the interferon. While all linker lengths function in the present invention, some linkers are somewhat more effective that others, i.e., linkers with 12 or more amino acids are somewhat more active than the shorter lengths. Preferably, the peptide linker has from 12 to 15 amino acids or from about 17 to 40 amino acids.
  • SEQ ID NO: 1 The complete nucleotide sequence of an IFN ⁇ -Fc hybrid with no linker is shown in SEQ ID NO: 1 and the amino acid sequence is shown in SEQ ID NO:2.
  • the linker if present, is located between amino acid residue numbers 188 (Glu) and 189 (Glu).
  • the preferred embodiment of the present invention is a protein hybrid comprising an interferon protein covalently linked at its C-terminal end to the N-terminal end of an immunoglobulin Fc fragment.
  • the present invention also includes a protein hybrid comprising an immunoglobulin Fc fragment covalently linked at its C-terminal end to the N- terminal end of an interferon protein.
  • proteins can be linked directly or through a peptide linker as described herein.
  • the present invention also provides a protein hybrid homodimer comprising two interferon proteins covalently linked at their C-terminal end to each of the two N-terminal ends of an immunoglobulin Fc fragment, preferably a ⁇ 4 Fc fragment, or a protein hybrid homodimer comprising two interferon proteins covalently linked at their C-terminal end to the N-terminal end of a peptide linker that is covalently linked at their C-terminal end to each of the two N-terminal ends of an immunoglobulin Fc fragment.
  • the linkers can contain the same number of amino acids or a different number of amino acids.
  • the hybrid can comprise interferon and from 1 to 10 cytokines, including multiple interferons.
  • Suitable cytokines include, but are not limited to, interleukins, Colony Stimulating Factor, and Tumor Necrosis Factor.
  • an interferon protein is linked, directly or through a linker, to one of the two N-terminal ends of an immunoglobulin Fc fragment and another cytokine is linked, directly or through a linker, to the other of the two N-terminal ends of an immunoglobulin Fc fragment.
  • hybrids of the present invention over the native cytokine are those that have been shown to ablate tumors in an animal model.
  • IFN ⁇ is approved for use in treating certain tumors and hepatitis B.
  • the hybrids may be more effective than IFN ⁇ in treating infectious diseases and a broad range of tumors.
  • the IFN ⁇ cDNA can be obtained by reverse transcription and PCR using RNA extracted from cells that express IFN ⁇ and following the extraction with reverse transcription and expression in a standard expression system.
  • RNA extracted from cells that express IFN ⁇ and following the extraction with reverse transcription and expression in a standard expression system.
  • There are several ways to express the recombinant protein in vitro including in E. coli, baculovirus, yeast, mammalian cells or other expression systems.
  • the prokaryotic system, E. coli is not able to do post-translational modification, such as glycosylation. This could be a problem in these systems, and mammalian expression could be preferred for this reason, and because it offers other advantages in terms of simplifying purification.
  • the hybrids of the invention have a longer half-life in vivo than native IFN ⁇ based on in vitro experimental results. Even though the specific activity is lower, the hybrids are preferred to the native IFN ⁇ for clinical use. This is because, as a result of the longer half-life, the Cxt (the area under the concentration vs. time curve) is much greater based on in vitro results than for the native IFN ⁇ . This means that at the equivalent molar dosage of the native EFN ⁇ and the hybrid, the latter would provide a several hundred fold increased exposure to IFN ⁇ resulting in vastly increased efficacy at the same dosage and less frequent administration.
  • Immunoglobin Fc fragments useful in the present invention can be obtained by conventional methods well known to skilled artisans.
  • Peptide linkers useful in the present invention can be obtained by conventional methods well known to skilled artisans, including chemical synthesis and recombinant expression of the linker with the interferon and Fc fragment.
  • the IFN ⁇ -Fc hybrids of the present invention have a much longer half-life in vivo than the native IFN ⁇ .
  • Cytokines are generally small proteins with relatively short half-lives. They usually dissipate rapidly among various tissues, including at undesired sites. It is believed that small quantities of some cytokines can cross the blood-brain barrier and enter the central nervous system and cause severe neurological toxicity.
  • the IFN-Fc hybrids of the present invention are especially suitable for treating tumors, including lymphomas and leukemias, because these products will have a long retention time in the vasculature and will not penetrate undesired sites.
  • the hybrids of the present invention are therefore useful for treating patients with tumors to remove tumors, regress tumors, or delay tumor development.
  • the hybrids are administered in amounts effective to treat the patient with tumors.
  • the determination of the dosage is within the skill of the art based upon the patient size, tumor size, tumor type, and similar parameters.
  • the IFN-Fc hybrids can be administered in a pharmaceutical formulation including suitable excipients and additives.
  • the dosage for human use can be readily determined by extrapolation from animal data, with compensation for differences in size, and routine experimentation in clinical trials.
  • the clearance half-life after subcutaneous (s.c.) administration of the hybrid was almost 120 fold longer.
  • the hybrid, when administered s.c, was also well absorbed.
  • the large increase in the AUC (area under curve) for the new hybrid means that it likely would be more efficacious than native interferon- ⁇ , notwithstanding its lower specific activity.
  • IFN- ⁇ (16)Fc contains IFN ⁇ linked to the hinge region of the human IgG4 Fc fragment through the sixteen amino acid peptide linker shown in SEQ ID NO: 11, an amino acid sequence as follows: GlyGlySerGlyGlySerGlyGlyGlyGlyGlySerGlyGlyGlyGlyGlySer.GlyGlySer.
  • the IFN- ⁇ - Ala-Fc construct contains IFN- ⁇ linked to the hinge region of the human IgGl Fc with one amino acid (Ala) between the two domains.
  • DNA fragments encoding IFN- ⁇ (16)Fc and IFN- ⁇ -Ala-Fc were inserted, respectively, at the polycloning site of the pcDNA3 expression plasmid.
  • Purified plasmid DNA was then used to transfect NS0 cells by electroporation. Stably-transformed cell lines were selected in the presence of G418. Cell lines expressing these linker variants were then grown in spinner culture flasks. Spent culture supernatant was collected and purified proteins were prepared using the protein A affinity column. Purified proteins were used in the same virus cytopathic effect inhibition assays as described in Example 1. Both IFN- ⁇ - Ala-Fc and IFN- ⁇ (16)Fc were shown to have equivalent activities ( Figure 1).
  • IFN ⁇ -Fc interferon- ⁇ linked to an Fc
  • DNA sequences containing different IFN ⁇ -Fc linker variants were inserted, respectively, at the polycloning site of the pcDNA3 expression plasmid. Purified DNA was then used to transfect NSO cells by electroporation. Stably-transformed cell lines were initially selected in the presence of G418. Cell lines expressing these linker variants were then grown in the absence of G418. Spent culture supernatant was collected and filtered through a 0.22 ⁇ m membrane. The concentration of IFN ⁇ -Fc was estimated by PCFIA using purified EFN ⁇ -Fc protein as the standard.
  • human lung carcinoma A549 cells were plated at lOO ⁇ l/well containing 5x10 4 cells using DMEM containing 5% FBS. Plates were incubated at 37°C for 24 hrs in the 5% CO 2 incubator. Culture supernatants containing the IFN ⁇ -Fc linker variants were diluted. These solutions were then used to make 2-fold serial dilutions in a 96-well plate using DMEM containing 5% FBS. One hundred ⁇ l of the diluted samples were added to each well and the plates were incubated at 37°C for an additional 24 hours in the incubator.
  • mice Female CB17/scid mice (Charles River Laboratories; seven and half weeks old) were inoculated subcutaneously (s.c.) with Daudi Burkitt lymphoma cells at the lower right flarik at a total volume of 100 ⁇ l. There were four different cell densities tested in five animals in each group (Table 2). The injection site was monitored one day after inoculation and then daily three weeks after inoculation.
  • cells were grown in vitro in D15 media with 10% fetal calf serum inlOO ml spinners to a density of 0.6X106/ml with 94% viability. Cells were harvested by centrifugation at 300g for 10 minutes, washed twice in cold PBS, and resuspended to the desired density in PBS. Cell counting and Tryptan Blue staining confirmed the cell density and viability.
  • the take rate reached 60% by the end of the nine and half weeks.
  • the tumors did not kill the mice and there was no sign of metastases.
  • mice inoculated with 12.5X10 6 Daudi Burkitt lymphoma cells were randomly assigned to one of four treatment groups as shown in Table 3.
  • Roferon A IFN- ⁇ - 2a, Hoffmann La Roche, Nutley, NT
  • IFN- ⁇ (16)-2a-Fc having the linker shown in SEQ ID NO: 11
  • treatment began the day after tumor inoculation. All the animals were dosed daily subcutaneously over the scruff and the treatment continued for eight consecutive weeks. During the treatment period, animals were monitored every 3-4 days for tumor development, and tumor size was measured as above. After the treatment period, weekly observations were continued for additional six months for animals that were tumor free by the time when treatment stopped.
  • Serum Interferon level was determined by ELISA.
  • Tumor development in different treatment groups is shown in Table 4.
  • the first tumor was detected 24 days after inoculation and within 6 days thereafter 7/8 (87.5%) of the animals had developed tumors.
  • the average time of tumor detection was 25.1+ 2.3 days (The mouse that developed a tumor at day 75 was not included.).
  • the first tumor became detectable 32 days after the inoculation. After another two weeks, 87.5% had developed tumors.
  • the average tumor detection time was 39.6+4.7 days (t>t 0 . 05 ( i 2) , PO.05).
  • Roferon A delayed tumor development for about two weeks.
  • IFN- ⁇ -2a-Fc treatment at both doses completely prevented the Daudi lymphoma from developing throughout the entire dosing period.
  • two mice developed detectable tumors at 2 and 19 days after cessation of the treatment. While all mice in 1x10 IU/day group and the remaining six mice in 1X10 5 IU/daily still remained tumor free six months post treatment. (Table 4). This experiment was repeated once with similar results, as shown in Table 4.
  • IFN- ⁇ -2a-Fc Quantization of Serum EFN- ⁇ Level Serum concentration of IFN- ⁇ and IFN- ⁇ -2a-Fc was determined by ELISA procedures. In Roferon A treated mice, IFN- ⁇ -2a was undetectable 24 hours after the last dose. In IFN- ⁇ -2a-Fc treated mice, serum IFN- ⁇ -2a-Fc concentration was 3.5 ug/ml for thelxlO 6 IU/day group and 0.7 ug/ml for the lxlO 5 IU/day group 22 days after termination of the treatment (Table 6). There was a decrease in serum concentration between 1 and 22 days after the end of the treatment. The data indicate that IFN- ⁇ -2a-Fc has a half-life of about one week in mice after being administered subcutaneously 1X10 6 IU/day or 1X10 5 IU/day for 8 weeks.
  • a murine human tumor xenograft model has been established by inoculating subcutaneously female CB17/scid mice (six and half weeks old) with 1.25X10 7 Daudi Burkitt lymphoma cells in the lower right flank at a total volume of 100 ⁇ l.
  • IFN- ⁇ -2a-Fc has a half-life of about one week, when administered subcutaneously 1X10 6 IU/day or 1X10 5 IU/day for eight weeks.

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  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Chemical & Material Sciences (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des protéines de fusion interféron-immunoglobuline Fc (« hybrides IFN-Fc ») qui sont utiles pour enlever ou faire régresser des tumeurs ou pour retarder leur évolution. Ces hybrides comprennent de préférence des peptides de liaison entre l'IFN et le fragment Fc. Ces lieurs sont des séquences inertes de lymphocytes T ou une séquence non-immunogène quelconque, de préférence des unités de répétition Gly-Ser. Le fragment Fc préféré est un fragment Fc d'immunoglobuline humain, de préférence la chaîne η4.
EP02753441A 2002-08-07 2002-08-07 Hybride d'interferon et de fragment fc d'immunoglobuline Withdrawn EP1536825A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2002/025154 WO2004022088A1 (fr) 1999-10-15 2002-08-07 Hybride d'interféron et de fragment fc d'immunoglobuline

Publications (2)

Publication Number Publication Date
EP1536825A1 true EP1536825A1 (fr) 2005-06-08
EP1536825A4 EP1536825A4 (fr) 2007-09-12

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EP02753441A Withdrawn EP1536825A4 (fr) 2002-08-07 2002-08-07 Hybride d'interferon et de fragment fc d'immunoglobuline

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EP (1) EP1536825A4 (fr)
AU (1) AU2002313730A1 (fr)
CA (1) CA2495480A1 (fr)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO2004022088A1 *

Also Published As

Publication number Publication date
AU2002313730A1 (en) 2004-03-29
EP1536825A4 (fr) 2007-09-12
CA2495480A1 (fr) 2004-03-18

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