EP0586505A1 - Anticorps d'heteroconjugues pour le traitement des infections a l'hiv - Google Patents

Anticorps d'heteroconjugues pour le traitement des infections a l'hiv

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Publication number
EP0586505A1
EP0586505A1 EP19920911846 EP92911846A EP0586505A1 EP 0586505 A1 EP0586505 A1 EP 0586505A1 EP 19920911846 EP19920911846 EP 19920911846 EP 92911846 A EP92911846 A EP 92911846A EP 0586505 A1 EP0586505 A1 EP 0586505A1
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EP
European Patent Office
Prior art keywords
cells
hiv
antibody
cem
infected
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EP19920911846
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German (de)
English (en)
Inventor
Paul J. Higgins
Barbara J. Potts
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Repligen Corp
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Repligen Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], 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
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to the treatment of Human Immunodeficiency Virus infection.
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immunodeficiency Syndrome
  • the amino acid sequence of the HIV envelope glycoprotein gpl20 is particularly variable; its amino acid sequence can vary by 20-25% from one strain to the next.
  • strain to strain variability there is a more subtle variation in genome sequence caused by the high error rate of reverse transcriptase.
  • the misincorporation rate is high enough to introduce one error per genome per replication cycle. Consequently any particular viral isolate consists of a cohort of quasi- species.
  • the diversity and number of quasi- species apparently differs from one HIV variant to another. There is substantial evidence that these quasi- species evolve in vivo. For example, successive viral isolates from an infected individual reveal substantial temporal fluctuations in the proportion of various quasi- species (Meyehans, Cell 58:901, 1989).
  • cytotoxic hybrid proteins composed of a cytotoxin fused to part of the CD4 receptor have been proposed as a way to destroy cells expressing HIV encoded proteins.
  • This approach relies on the fact that the HIV envelope protein, gpl20, recognizes the CD4 receptor, which is present on T4 lymphocytes and certain cells of the monocyte/macrophage lineage.
  • a soluble derivative of CD4 might be used to target a cytotoxin to HIV infected cells that express surface gpl20.
  • Heteroconjugate molecules consisting of two covalently joined antibodies or an antibody covalently joined to a cell- or virus-targeted protein have been proposed as a means by which to target cytotoxic cells to undesirable cells such as tumor cells and virally infected cells.
  • Segal et al. U.S. Patent No. 4,676,980
  • Fanger et al. PCT publication WO91/00360
  • Fanger et al. have proposed such heteroconjugates for treatment of AIDS.
  • Fanger et al. suggest the use of a high affinity Fey receptor-specific antibody fused to CD4 (or the CD4 binding domain of gpl20) for AIDS therapy.
  • Fanger et al. also suggest the use of heteroantibodies consisting of an high affinity FCT receptor-specific antibody fused to an HIV-specific antibody such as anti- gpl20 antibody for AIDS therapy.
  • Zarling et al. (EP Publication No. 03089.36) described heteroconjugate antibodies consisting of an antibody specific for an HIV antigen that is expressed on HIV infected cells cross ⁇ linked to a second antibody which is specific for an effector cell of the peripheral blood and which is capable of killing HIV infected cells.
  • the invention features a heteroconjugate antibody which includes a first and a second portion joined together covalently, the first portion includes an antibody directed against an antigen present on the surface of an effector cell of the peripheral blood, the second antibody portion includes an antibody directed against a V3 loop sequence of the gpl20 envelope protein of HIV MN or a HIV MN viral variant expressed on the surface of HIV-infected cells, wherein the heteroconjugate antibody at an initial concentration of 20 ng/ml in a first mixed cell culture which includes effector cells and CEM-ss cells infected with HIV-MN decreases the reverse transcriptase activity of the first mixed culture cell by at least 80% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes effector cells and the CEM-ss cells infected with HIV-MN, wherein the effector cells are in 3-fold excess over the CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection
  • the decrease in the reverse transcriptase activity of the first cell culture is greater than 90% compared to the reverse transcriptase activity of the second mixed cell culture.
  • the heteroconjugate antibody at an initial concentration of 200 ng/ml in a first mixed cell culture which includes effector cells and CEM-ss cells infected with an HIV strain other than HIV-MN decreases the reverse transcriptase activity of the first mixed culture cell by at least 50% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes effector cells and said CEM-ss cells infected with the HIV strain other than HIV-MN, wherein the effector cells are in 3-fold excess over said CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection, the heteroconjugate antibody and the effector cells are added to said CEM-ss cells in the first mixed cell culture 18 hours after infection, and the first and second cell cultures are infected with 100- 1000 infectious units of the HIV strain other than HIV- MN.
  • the heteroconjugate antibody binds to the V3 loop of an HIV strain other than HIV-MN.
  • the effector cell is chosen from the group consisting of cytotoxic T lymphocytes, neutrophils, monocytes/macrophages, and large granular lymphocytes; and the antigen present on the surface of an effector cell is CD3.
  • the heteroconjugate antibody at an initial concentration of 20 ng/ml in a first mixed cell culture which includes effector cells and CEM-ss cells infected with HIV-III B decreases the reverse transcriptase activity of the first mixed culture cell by at least 80% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes effector cells and the CEM-ss cells infected with HIV-III B , wherein the effector cells are in 3-fold excess over the CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection, the heteroconjugate antibody and the effector cells are added to the CEM-ss cells in the first mixed cell culture 18 hours after infection, and the first and second cell cultures are infected with 100-1000 infectious units of HIV-III B .
  • the invention features a heteroconjugate antibody which includes a first and a second portion joined together covalently, the first portion includes an antibody directed against an antigen present on the surface of an effector cell of the peripheral blood, the second antibody portion includes an antibody directed against a V3 loop sequence of the gpl20 envelope protein of HIV MN or a HIV MN viral variant expressed on the surface of HIV-infected cells, wherein the heteroconjugate antibody at an initial concentration of 10 ng/ml in a first mixed cell culture which includes the effector cells and CEM-ss cells infected with HIV-MN decreases the reverse transcriptase activity of the first mixed culture cell by at least 80% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes the effector cells and the CEM-ss cells infected with HIV-MN, wherein the effector cells are in 3-fold excess over the CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection
  • the invention feature a heteroconjugate antibody which includes a first and a 5 second portion joined together covalently, the first portion includes an antibody directed against an antigen present on the surface of an effector cell of the peripheral blood, the second antibody portion includes an antibody directed against a V3 loop sequence of the gpl20
  • I'D decreases the reverse transcriptase activity of the first mixed culture cell by at least 80% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes effector cells and the CEM-ss cells infected with HIV-MN, wherein the
  • effector cells are in 3-fold excess over the CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection, the heteroconjugate antibody and the effector cells are added to the CEM-ss cells in the first mixed 5 cell culture 18 hours after infection, and the first and second cell cultures are infected with 100-1000 infectious units of HIV-MN.
  • the invention features a heteroconjugate antibody which includes a first and a 0 second portion joined together covalently, the first portion includes an antibody directed against an antigen present on the surface of an effector cell of the peripheral blood, the second antibody portion includes an antibody directed against a V3 loop sequence of the gpl20 5 envelope protein of HIV MN or a HIV MN viral variant expressed on the surface of HIV-infected cells, wherein the heteroconjugate antibody at an initial concentration of 1 ng/ml in a first mixed cell culture which includes effector cells and CEM-ss cells infected with HIV-MN decreases the reverse transcriptase activity of the first mixed culture cell by at least 80% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes effector cells and the CEM-ss cells infected with HIV-MN, wherein the effector cells are in 3-fold excess over the CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection
  • the invention features a heteroconjugate antibody which includes a first and a second portion joined together covalently, the first portion includes an antibody directed against an antigen present on the surface of an effector cell of the peripheral blood, the second antibody portion includes an antibody directed against the amino acid sequence GPGRAF.
  • the heteroconjugate antibody at an initial concentration of 20 ng/ml in a first mixed cell culture which includes effector cells and CEM-ss cells infected with HIV-MN decreases the reverse transcriptase activity of the first mixed culture cell by at least 80% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes cells and the CEM-ss cells infected with HIV-MN, wherein the effector cells are in 3-fold excess over the CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection, the heteroconjugate antibody and the effector cells are added to the CEM-ss cells in the first mixed cell culture 18 hours after infection, and the first and second cell cultures are infected with 100-1000 infectious units of HIV-MN.
  • the heteroconjugate antibody at an initial concentration of 20 ng/ml in a first mixed cell culture which includes effector cells and CEM-ss cells infected with HIV-MN decreases the reverse transcriptase activity of the first mixed culture cell by at least 80% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes effector cells and the CEM-ss cells infected with HIV-MN, wherein the effector cells are in 3-fold excess over the CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection, the heteroconjugate antibody and the effector cells are added to the CEM-ss cells in the first mixed cell culture 18 hours after infection, and the first and second cell cultures are infected with 100-1000 infectious units of HIV-MN.
  • the invention features a heteroconjugate antibody which includes a first and a second portion joined together covalently, the first portion includes an antibody directed against an antigen present on the surface of an effector cell of the peripheral blood, the second antibody portion includes an antibody directed against the amino acid sequence QARILAVERY KDQQLLGIWGCSGKLIC.
  • the heteroconjugate antibody at an initial concentration of 20 ng/ml in a first mixed cell culture which includes effector cells and CEM-ss cells infected with HIV-MN decreases the reverse transcriptase activity of the first mixed culture cell by at least 80% compared to the reverse transcriptase activity of an otherwise identical second mixed cell culture which includes effector cells and the CEM-ss cells infected with HIV-MN, wherein the effector cells are in 3-fold excess over the CEM-ss cells in the first and second mixed cell cultures, the reverse transcriptase activity is measured ten days after infection, the heteroconjugate antibody and the effector cells are added to the CEM-ss cells in the first mixed cell culture 18 hours after infection, and the first and second cell cultures are infected with 100-1000 infectious units of HIV-MN.
  • the effector cell is chosen from the group consisting of cytotoxic T lymphocytes, neutrophils, mono ⁇ ytes/macrophages, and large granular lymphocytes; and the antigen present on the surface of an effector cell is CD3.
  • the invention features a pharmaceutically acceptable composition which includes a pharmaceutically effective amount of a heteroconjugate antibody described above.
  • the invention features a method for treating a patient infected with HIV, the method includes administering to the patient the above- described pharmaceutically acceptable composition.
  • the invention features an HIV- targeted effector cell which includes: (a) an effector cell expressing a cell surface antigen; and (b) an above- described heteroconjugate antibody.
  • the invention features a method for treating a patient infected with HIV; the method includes administering to the patient the above- described HIV-targeted effector cell.
  • the MN prototype virus is defined by a particular amino acid subsequence within the V3 loop region of the gpl20 envelope protein having positions A j -A ⁇ K-R-K-R-I- H-I-G-P-G-R-A-F-Y-T-T-K.
  • Amino acid sequences are presented in the standard single-letter code throughout.
  • MN viral variants are variant which exhibit complete amino acid sequence homology at residues I-G-P-G-R, i.e., at positions A ? through A X1 , and at least 36% homology with the remaining 12 amino acids of the HIV-MN sequence given above.
  • directed against is meant that an antibody binds to the indicated antigen.
  • the V3 loop of gpl20 is defined as the 36 amino acid region from amino acid 303 to 338, inclusive, according to the gpl20 numbering scheme of Ratner et al. (Nature 313:277, 1985).
  • heteroconjugate antibodies of the invention are highly effective; even at low concentrations they are capable of nearly eliminating viral replication as judged by a reverse transcriptase assay.
  • the preferred heteroconjugate antibodies are those which are effective against more than one strain.
  • Figure 1 is a graphical representation of the effect of a mixture of unconjugated OKT3 antibody and 59.1 antibody (filled diamonds) and OKT3/59.1 heteroconjugate antibody (open squares) on the reverse transcriptase activity of CEM-ss cells infected with HIV- III B in the presence of cytotoxic T-lymphocytes.
  • Reverse transcriptase activity (cpm/10 ⁇ l) is presented as a function of the initial antibody concentration (ng/ml) in the cell culture.
  • Figure 2 is a graphical representation of the effect of a mixture of unconjugated 0KT3 antibody and 59.1 antibody (filled diamonds) and OKT3/59.1 heteroconjugate antibody (open squares) on the reverse transcriptase activity of CEM-ss cells infected with HIV- MN in the presence of cytotoxic T-lymphocytes.
  • Reverse transcriptase activity (cpm/10 ⁇ l) is presented as a function of the initial antibody concentration (ng/ml) in the cell culture.
  • Figure 3 is a graphical representation of the effect of a mixture of unconjugated 0KT3 antibody and 59.1 antibody (open circles) and OKT3/59.1 heteroconjugate antibody (filled circles) on the reverse transcriptase activity of CEM-ss cells infected with HIV- III B in the absence of cytotoxic T-lymphocytes.
  • the reverse transcriptase activity of HIV-III B infected CEM- ss cells in the presence of cytotoxic lymphocytes only (filled triangle) ; HIV-III B infected CEM-ss cells alone (open triangle) ; and uninfected CEM-ss cells alone (filled square) is also indicated.
  • Reverse transcriptase activity (cpm/10 ⁇ l) is presented as a function of the initial antibody concentration (ng/ml) in the cell culture (except for those cases in which no antibody was added) .
  • Figure 4 is a graphical representation of the effect of the ratio of cytotoxic T-lymphocytes to HIV-MN infected CEM-ss cells on reverse transcriptase activity in the presence of 1 ⁇ g/ml OKT3/59.1 heteroconjugate antibody.
  • Reverse transcriptase activity (cpm/10 ⁇ l) is presented as a function of the cytotoxic lymphocyte to CEM-ss cells (log 10 scale) .
  • Figure 5 is a set of graphs which illustrate the effect of cytotoxic T-lymphocytes and OKT3/59.1 heteroconjugate antibody (open squares) and a mixture of unconjugated OKT3 antibody and 59.1 antibody (filled triangles) on the reverse transcriptase activity of CEM- ss cells infected with HIV-MN (panel A) , HIV-Alabama (panel B) , HIV-Duke 7887-7 (panel C) , HIV-Duke 6587-5 (panel D) , HIV-Duke 6587-7 (panel E) , HIV-III B (panel F) , HIV-SF2 (panel G) , and HIV-WMJ2 (panel H) .
  • a control is included where neither antibodies or cytotoxic T-lymphocytes were added (filled circles) .
  • Reverse transcriptase activity (cpm/10 ⁇ l) is presented as a function of the number of days post-infection.
  • Figure 6 is a graphical representation of the effect of a mixture of conjugated 0KT3 antibody and 6C5 antibody (open circles) and OKT3/6C5 heteroconjugate antibody (filled circles) on the reverse transcriptase activity of HIV-III B infected CEM-ss cells.
  • Reverse transcriptase activity (cpm/10 ⁇ l) is presented as a function of the initial antibody concentration (ng/ml) in the cell culture.
  • the molecules of the invention are heteroconjugate antibodies produced by covalently attaching a first antibody which is directed against an antigen present on the surface of a cytotoxic immune effector cell capable of killing an HIV infected cell to a second antibody which is directed against an HIV antigen present on the surface of HIV infected cells.
  • the heteroconjugate antibodies of the invention are highly potent. Even at relatively low concentrations, these heteroconjugate antibodies are capable of substantially reducing HIV activity in a mixed cell culture of HIV infected cells and effector cells.
  • the most preferred heteroconjugate antibodies are those which are both highly potent and broadly reactive. Broadly reactive heteroconjugate antibodies are those which are effective against more than one strain of HIV. For example, a broadly reactive heteroconjugate antibody might be effective against HIV-MN and HIV-SF2 or HIV-MN and HIV-WMJ2, or HIV-MN and HIV-III B .
  • the portion of the heteroconjugate antibody which is directed against a cytotoxic immune effector cell capable of killing HIV infected cells recognizes an antigen present on the surface of cells such as: cytotoxic T-lymphocytes, monocytes/macrophages, large granular lymphocytes (including cells and NK cells) , and neutrophils.
  • the immune effector cell- directed antibody binds to an antigen on the surface of the effector cell in a manner which triggers cytolytic activity.
  • the antigen recognized can be the CD3 receptor or the CD16 (Fc) receptor.
  • Fc CD16
  • antibodies directed to receptors which require multiple signals to initiate cytolytic activity e.g., the CD2 and CD28 receptors
  • the portion of the heteroconjugate antibody which is directed against an antigen present on the surface of HIV infected cells preferably recognizes: (1) an epitope within the V3 loop sequence of the gpl20 envelope protein of the MN prototype of HIV-1 (HIV-MN); (2) an epitope within the V3 loop sequence of the gpl20 envelope protein of a viral variant of the MN prototype of HIV-1; or (3) an epitope within the portion of gp41 between amino acids 584 to 611, inclusive.
  • the V3 loop of gpl20 is the 36 amino acid region from amino acid 303 to 338, inclusive, according to the gpl20 numbering scheme of Ratner et al. (Nature 313:277, 1985) .
  • MN prototype of HIV-1 is defined by the following amino acid subsequence within the V3 loop of gpl20: K-R-K-R-I-H-I-G-P-G-R-A-F-Y-T-T-K (A 1 -A 17 ) .
  • MN viral variants are variants which exhibit complete amino acid homology at residues I-G-P-G-R, i.e., positions A 7 through A 11 , and at least 36% homology with the remaining 12 amino acids of the MN sequence given above.
  • the above-described HIV-directed antibodies are good candidates for use in generating heteroconjugate antibodies which are highly potent. In some cases, however, the heteroconjugates formed will not be highly potent.
  • the usefulness of a particular HIV- directed antibody for production of a heteroconjugate antibody of the invention can only be assessed by producing a heteroconjugate antibody, for example by covalently linking the HIV-directed antibody to an anti- CD3 antibody, and measuring the potency of the heteroconjugate antibody in an appropriate assay.
  • a particular HIV-directed antibody has been shown to be useful for generating a potent heteroconjugate antibody, it can be used to generate other heteroconjugate antibodies by covalently linking it to other effector cell antigen-directed antibodies.
  • heteroconjugate antibodies are those which are broadly reactive as well as highly potent.
  • HIV-directed antibodies which recognize: (1) an epitope having the sequence G-P-G-R-A-F; (2) an epitope having the sequence I-X-I-G-P-G-R, where X is any amino acid; or (3) an epitope within the portion of gp41 between amino acids 584 to 611 (according to the numbering scheme of Ratner et al., supra) , inclusive are likely to be useful for generating highly potent and broadly reactive heteroconjugate antibodies.
  • In order to generate broadly reactive heteroconjugate antibodies it is useful to select HIV-directed antibodies which recognize a broad range of HIV strains (i.e., antibodies which are not strain specific) . It is also useful to select antibodies which are directed against the amino acid sequence: G-P- G-R-A-F; or the amino acid sequence: I-X-I-G-P-G-R, where X is any amino acid; or an epitope within the portion of gp41 from amino acid 584 to amino acid 611. These antibodies can be identified using standard epitope mapping techniques as described below.
  • the steps for generating and selecting useful HIV-directed antibodies include: (1) generation of hybridomas and selection of hybridomas producing reactive antibodies; (2) selection of hybridomas producing antibodies capable of binding to cells expressing HIV envelope protein; (3) amplification and purification of selected monoclonal antibodies; (4) analysis of antibody reactivity using gpl20 V3 loop peptides or gp41 derived peptides; and (5) epitope mapping.
  • steps 1 through 3 it is possible to simply follow steps 1 through 3 and use the purified antibodies to prepare heteroconjugate antibodies whose potency and breadth of reactivity can be analyzed using the reverse transcriptase assay described herein below.
  • a purified HIV-directed antibody is covalently attached to an antibody directed against an immune effector cell.
  • the potency and reactivity of heteroconjugate antibodies can be measured in a mixed cell culture of effector cells and HIV-infected cells using a reverse transcriptase assay.
  • Heteroconjugate antibodies may be formed using any convenient cross-linking method. Suitable cross-linking methods include: SPDP, SPDP and SMCC, and biotin-avidin. Segal et al. (U.S. Patent 4,676,980) describes a number of cross-linking techniques. Alternatively, the antibodies can be linked by the generation of bispecific antibodies via hybrid-hybridomas (Suresh et al.. Methods in Enzymology 121:210, 1896) or by genetic engineering. Preparation of HIV-directed Antibodies
  • Antibodies useful for the preparation of the heteroconjugate molecules of the invention may be generated and screened as described below. Methods for preparing and analyzing antibodies directed towards the V3 loop of HIV-MN of an HIV-MN viral variant are also described in U.S. Application No. 07/665,306, filed March 6, 1991, hereby incorporated by reference. Preparation of the Immunogen
  • the immunogen used to generate these antibodies can include: gpl60, gpl20, fragments of gpl20 or gpl60 which include all or part of the V3 loop, or synthetic peptides which include all or part of the V3 loop.
  • the V3 loop sequences is that of HIV- MN or an HIV-MN viral variant.
  • Preferred immunogens for generating V3 loop directed antibodies include the RP70 peptide formed into a closed loop (described below) .
  • the other group of HIV-directed antibodies useful for production of heteroconjugate antibodies recognize sequences within the region of gp41 spanning amino acids 584-611.
  • the immunogens used to generate these antibodies can include: gpl ⁇ o, gp41, and fragments of gpl ⁇ o or gp41 which include all or part of the sequence lying between amino acids 584 and 611 of gp4l, i.e., Q- A-R-I-L-A-V-E-R-Y-L-K-D-Q-Q-L-L-G-I-W-G-C-S-G-K-L-I-C.
  • the immunizing peptide, polypeptide or protein may be in linear form or alternatively may contain the V3 loop formed into a closed loop by creation of a disulfide bond between cysteine residues at the termini of the V3 loop sequence. If the immunizing peptide contains more than one V3 loop, each may be separately formed into a loop through disulfide bonding.
  • Synthetic peptides containing the desired sequences can be synthesized by automated peptide synthesis using an automated peptide synthesizer.
  • Intact recombinant gpl60 envelope polypeptide can be produced in insect cells using a baculovirus expression system and purified as described in Rusche et al., U.S. Application No. 091,481, filed August 31, 1987, assigned to the same assignee as the present invention, hereby incorporated by reference.
  • Synthetic peptides or protein fragments to be used as immunogens can be either unconjugated or conjugated to an immunogenic carrier, e.g. , keyhole limpet hemocyanin (KLH) or ovalbumin, using succinyl maleimidomethyl cyclohexanylcarboxylate (SMCC) as a conjugation agent (Yoshitake et al., J. Biochem. 92:1413, 1982), as follows.
  • an immunogenic carrier e.g. , keyhole limpet hemocyanin (KLH) or ovalbumin
  • KLH keyhole limpet hemocyanin
  • SMCC succinyl maleimidomethyl cyclohexanylcarboxylate
  • SMCC SMCC dissolved in 50 ⁇ l of dimethylformamide
  • carrier at a concentration of 10-20 mg/ml in 0.1M NaP0 4 , pH 6.5
  • the solution is then passed through a Sephadex G-25 column to remove excess unreacted SMCC and 2 mg of peptide is added (suspended in a degassed solution of 0.1M NaP0 4 , pH 8, lmM EDTA at a concentration of 10 mg/ml) .
  • the solution is mixed by N, gas and incubated at 4°C overnight.
  • the sample is then dialyzed in 6M urea, 0.1M NaP0 4 , pH 7 until the precipitate dissolves.
  • the sample is next eluted through a BioGel P-10 column equilibrated in 6M urea, 0.1M NaPO..
  • the voided protein is collected and dialyzed in distilled H_0.
  • Peptides RP70, RP123C, and RP174c can be formed into closed loops by creation of a disulfide bond between the two cysteine residues near the ends of the amino acid sequence.
  • a method for creating such a bond is described in. Zhang et al. (Biochemistry 27:3785, 1988).
  • the peptides were prepared for immunization by emulsification in complete Freund's adjuvant according to standard techniques. (CFA, Difco Labs, Grand Island, NY) .
  • HIV-directed antibodies were prepared by intraperitoneal immunization of mouse strains (Balb/c, C57BL/6, A.SW, B10.BR, or BIO.A, Jackson Labs., Bar Harbor, ME) with 10-50 ⁇ g per mouse of circularized RP70 (Table 1) or recombinant gpl60.
  • mice were given booster immunizations of the immunogen, either in an emulsification of incomplete Freund's adjuvant or in soluble form, two to three times at two to four week intervals following the initial immunization. Mice were bled and the sera assayed for the presence of antibodies reactive with the immunogen.
  • mice showing a strong serological response were boosted and, 3-5 days later, spleen cells from these mice were fused with NS-1 (A.T.C.C. No. TIB18) , SP2-0 (A.T.C.C. No. CRL8287, CRL8006) , or P3.X63.AG8.653 myeloma cells incapable of secreting both heavy and light immunoglobulin chains
  • Each well of a 96-well Costar flat-bottom microtiter plate was coated with the peptide by placing a 50 ⁇ l aliquot of a PBS solution containing the peptide at a final concentration of 0.1-10 ⁇ g/ml in each well.
  • the peptide solution was aspirated and replaced with PBS + 0.5% BSA. Following incubation, the wells were aspirated, washed, and 50 ⁇ l of hybridoma supernatant was added.
  • Hybridomas that test positive by the ELISA method can be tested for their ability to bind to cells which express the HIV envelope protein.
  • recombinant vaccinia virus expressing a the env gene of a particular HIV strain are used to infect cells of the CD4+ human T-lymphoma line, CEM-ss (AIDS Research and Reference Reagent Program, Rockville, MD, catalog #776) .
  • Hybridoma supernatant (or purified antibodies) are incubated with the infected cells, and antibody binding is detected by indirect immune florescence using a secondary antibody and a florescence activated cell sorter.
  • binding to otherwise identical cells which do not express an HIV env gene is measured.
  • Hybridomas producing antibodies which bind to env expressing cells are then selected for further characterization.
  • Cells expressing the env gene of any HIV strain may be prepared as described below.
  • an assay for inhibition of syncytia formation can be used to assess HIV-directed antibodies.
  • the antibody is added to a mixture of HIV-infected and uninfected cells and giant cell formation is monitored. This assay is described in detail in U.S. Application No. 07/665,306, filed March 6, 1991, hereby incorporated by reference. Preparation of HIV env Expressing Cells Using a Recombinant Vaccinia Virus
  • An assay for binding to cells expressing an HIV env gene can employ cells infected with a vaccinia virus expressing an HIV env gene rather than actual HIV infected cells.
  • Construction of a recombinant vaccinia virus capable of expressing the full-length HIV envelope gene from a vaccinia virus promoter is described in EP Publication No. 0 243 029, hereby incorporated by reference.
  • the recombinant vector pSC25 containing the HIV env gene and the la ⁇ Z gene of E. coli expressed from a second vaccinia virus promoter, and flanked by vaccinia viral sequences which together encode thymidine kinase (TK) , was used to produce the recombinant virus.
  • TK thymidine kinase
  • a recombinant vector that contains DNA encoding an envelope gene having the specificity of the HIV-MN variant was prepared by removing a 570 bp Bglll fragment (encoding 180 amino acids) from the HIV-III-, env gene which spans the region of the VS loop in pSC25, and replacing it with the analogous Bglll fragment from the HIV-MN env gene.
  • the resulting plasmid, pSCR2502 contained a hybrid envelope gene which encoded an envelope protein having the principal neutralizing domain of the MN virus and the remainder of the env gene sequence from the HIV-III D- envelope.
  • a smaller region of the HIV-MN gpl60 protein can be used in place of the 180 amino acid replacement just described; e.g., DNA encoding the 36 amino acid V3 loop from any HIV strain can be inserted into the envelope- encoding DNA in place of the corresponding III ⁇ DNA sequence.
  • a recombinant could be used which contains the complete HIV-MN env gene. Multiple HIV envelope expressing strains are useful for assessing the specificity of an antibody.
  • the recombinant vector pSCR2502 was transfected into CV-1 host cells that had been pre-infected with vaccinia virus containing an intact TK gene.
  • the HIV envelope gene was integrated into the viral DNA by homologous recombination between the TK sequences on the vector and the TK sequences within the viral genome. Recombinants containing the HIV envelope gene were selected by infection of TK- cells and plating on media containing bromodeoxyuridine (BUdR) and X-gal.
  • BdR bromodeoxyuridine
  • BUdR is toxic to TK + cells and thus selects for TK " recombinants;
  • X-gal is a chromogenic substrate cleaved by the product of the lacZ gene which results in the production of blue plaques where the lacZ gene is expressed and further identifies the recombinant virus which also contains the HIV-env gene.
  • Antibody Purification and Amplification Hybridomas that tested positive for peptide binding in the ELISA assay were subcloned by the limiting dilution method.
  • Hybridoma cells and irradiated splenocytes from nonimmunized syngeneic mice were mixed and 200 ⁇ l of the mixed suspension were plated in microtiter wells to give 1 hybridoma cell per well. Subclones which appeared 7-14 days later were assayed again by the ELISA procedure described above. Representative positive subclones were subcloned a second time.
  • the isotypes of the antibodies were determined by the ELISA method using goat anti-mouse-HRP preparations which corresponded to each of the five major mouse immunoglobulin isotypes (IgM, IgGl, lgG2A, IgG2B and IgG3).
  • Purified antibodies were prepared by injecting hybridoma subclones that repeatedly tested positive by ELISA and syncytium inhibition assays intraperitoneally into pristane-primed syngeneic mice. The ascites which developed were recovered two to three weeks after injection and the monoclonal antibodies were purified as follows, using procedures which were dependent on the isotype of the antibody. Following elution, all IgG antibodies were dialyzed against PBS.
  • IgM antibodies were purified by 50% NH-SO. precipitation of ascites fluid from mice injected with the corresponding hybridoma cells, and then dialysis of the precipitate against 4X PBS. The dialyzed antibody was then passed over an Ultrogel A-6 column (Biotechnics, Villeneuve-La-Garenne, France) pre- equilibrated with 4X PBS. The antibody-containing fraction was identified using ELISA.
  • Assays described below can be used for determination of the strain specificity of HIV-directed antibodies and to map the epitope recognized by HIV- directed antibodies. Some or all of these assays may be used to select HIV-directed antibodies for production of heteroconjugate antibodies. The assay for binding to cells expressing an HIV env gene described above can also be used to assess antibody specificity. The epitope recognized by the V3-directed antibodies can be mapped using standard ELISA assays and competitive ELISA assays as described below.
  • Peptides which are useful for ELISA assays include: (1) a series of 24 or 25-mers representing the V3 loop sequences from a variety of HIV variants (Table 2) ; and (2) the MN substitution series, which includes a series of 12-mers corresponding to the MN V3 loop tip sequence (C)-K-R-I-H-I-G-P-G-R-A-F-Y-T-T- (C) , each having an alanine residue substituted for one of the amino acids starting at the first arginine (R) residue and proceeding to the tyrosine (Y) residue.
  • substitution series a glycine was substituted for the naturally occurring alanine.
  • Antibody recognition of an epitope contained within the MN sequence is revealed by loss of binding of the antibody to an alanine-substituted peptide, the alanine substitution having disrupted the binding interaction.
  • ELISA assays were performed as for standard ELISA assays with the following modifications. Prior to applying the antibody to the plate, the antibody preparation is incubated with a test peptide from the groups listed above at concentrations ranging from 10 ⁇ M to 0.0045 ⁇ M. If the test peptide competes with the immobilized immunogen for binding to the antibody, the ELISA will reveal little or no binding of the antibody to the plate.
  • the epitope recognized by gp41-directed antibodies can be mapped in a similar manner using an alanine substitution series based on the sequence of all or part of gp41. It is also possible to use peptides whose sequence corresponds to a portion of gp41.
  • Described below are two antibodies which recognizes sequences within the V3 loop of HIV-MN gpl20 and which can be used to generate heteroconjugate antibodies.
  • Hybridomas F59 and F83 were generated from immunization of BA B/C mice with the closed loop immunogen RP70 (Table 1) .
  • .Antibodies, designated F59/P5B3 (59.1), and F83/P6F12 (83.1) were identified as antibodies which are not strain specific. Alanine- ⁇ ubstituted peptides that were capable of competing with RP70 for binding to the 59.1 antibody did not contain alanine substitutions within the G-P-G-R-A-F sequence.
  • peptides that contained the G-P-G-R-A-F sequence were able to compete with RP70 for binding to the 59.1 antibody, while those that did not contain this sequence (i.e., RP129 and RP175) were not able to compete.
  • RP129 and RP175 were not able to compete.
  • the 59.1 antibody recognizes the G-P-G-R-A-F epitope.
  • This sequence is present in a wide range of HIV variants.
  • the strain specificity of the 59.1 antibody was analyzed using the above-described techniques. These assays indicated that 59.1 recognizes the V3 loop of HIV-MN, HIV-SF2, HIV-WMJ2 and HIV-III B .
  • ELISA assays demonstrated that the 83.1 antibody recognizes the I-X-I-G-P-G-R epitope (where X is any amino acid).
  • the strain specificity of the 83.1 antibody was analyzed using the above-described techniques. These assays indicated that 83.1 recognizes the V3 loop of HIV- MN, HIV-Alabama, HIV-SF2, HIV-WMJ2, and HIV-Duke 7887-7.
  • OKT3/59.1 and OKT3/6C5 were produced by covalently cross-linking an anti-CD3 monoclonal antibody, 0KT3, to a second monoclonal antibody, 59.1, directed against an epitope within the V3 domain of the gpl20 subunit of HIV- MN.
  • OKT3/6C5 heteroconjugate antibody was produced by covalently cross-linking OKT3, to a monoclonal antibody, 6C5, directed against a conserved epitope within residues 584-611 of the gp41 subunit of HIV (numbering according to Ratner et al. , Nature 313:277, 1985).
  • CD3 is a receptor closely associated with the T cell receptor for antigen (TCR) .
  • TCR TCR
  • donor PBL were incubated in bulk culture with an allogenic EBV-transformed lymphoblastoid cell line (stimulator cells) for 7 days in RPMI 1640 medium supplemented with 20% FBS (Gibco/BRL, Grand Island, NY) , supernatant derived from PHA-stimulated PBL, and 100 U/ml of recombinant interleukin-2.
  • the cells were then cloned by limiting dilution (1 cell/well) in U-bottom trays. Irradiated autologous PBL and stimulator cells were used as feeders.
  • the clones were screened for CTL activity (assessed by lysis of stimulator cells) and NK activity (lysis of K562 cells; CCL 243, American Type Culture Collection, Bethesda, MD) . Clone 1F8 possessing CTL activity and not NK activity was selected.
  • OKT3/59.1 Decreases Viral Replication as Measured by Reverse Transcriptase Activity in HIV-MN and HIV-III B Infected Cells
  • CEM-ss cells (15,000 cells/well in a 96 well plate) were infected with 64 infectious units (IU) of HIV-III B or HIV-MN.
  • effector cells (1F8 cells 45,000/well) along with varying concentrations of either OKT3/59.1 heteroconjugate or an equivalent amount of the unconjugated antibodies were added to the infected CEM- ss cells.
  • the CTL were grown in RPMI 1640 with 10% FBS; Gibco/BRL) , and were washed with fresh medium prior to addition of antibodies. After 7 days cell-free culture supernatants were harvested and assayed for reverse transcriptase activity by the method of Willey et al. (J. Virol . 62:139, 1988).
  • OKT3/59.1 heteroconjugate (filled diamonds) at 0.5 ng/ml essentially eliminated reverse transcriptase activity in CEM-ss cells infected with either HIV-III B or HIV-MN.
  • a mixture of unconjugated OKT3 antibody and 59.1 antibody (open squares) had no effect on the reverse transcriptase activity even at 2,000 ng/ml.
  • 0KT3/59.1 heteroconjugate has no effect on reverse transcriptase activity in the absence of CTL cells (filled circles) .
  • CTL in absence of OKT3/59.1 heteroconjugate (filled triangle) have no substantial effect on the reverse transcriptase activity of HIV-III B infected cells.
  • Unconjugated antibodies in the absence of CTL (open circles) and CTL alone (open triangle) have no substantial effect on the reverse transcriptase activity of infected cells.
  • Uninfected cells filled square have no detectable reverse transcriptase activity. In all cases CTL and/or antibodies were added 18 hr post-infection.
  • the period of HIV infection prior to the addition of antibody and CTL was varied to determine whether longer periods of viral replication and thus increased viral spread affects the efficacy of the heteroconjugate molecule.
  • CEM-ss cells were incubated with HIV-III B or HIV-MN (64 IU) for 6, 18, 48 or 72 hours prior to the addition of antibody and CTL.
  • Reverse transcriptase activity was measured 7 days post-infection. When infection proceeded for 6, 18 or 48 hours prior to the addition of 0KT3/59.1 heteroconjugate and CTL, 0.5 ng/ml of heteroconjugate was sufficient to completely eliminate reverse transcriptase activity.
  • the in vitro potency of OKT3/59.1 heteroconjugate was further characterized by an experiment in which the concentration of antibody was held constant, but the ratio of CTL to CEM-ss cells was varied.
  • concentration of OKT3/59.1 heteroconjugate (1 ⁇ g/ml), the number of CEM-ss cells (15,000/well) and the infectious dose (64 IU) of HIV-III B or HIV-MN were held constant, and the number of CTL added to the cultures was varied.
  • CTL and/or heteroconjugate antibody were added 18 hr post-infection and reverse transcriptase activity was measured 7 days post infection. Referring to Fig.
  • CEM-ss cells (150,000/well in 24 well plates) infected with 100-1000 IU of HIV.
  • CTL 450,000/well
  • 1 ⁇ g/ml of OKT3/59.1 heteroconjugate or 1 ⁇ g/ml of a mixture of monomeric antibodies
  • Cultures were split 3 times per week and culture supernatants were collected at four or five day intervals for assay of reverse transcriptase activity. After the initial addition of antibody no further antibody was added. Thus splitting the culture decreases the antibody concentration and the absolute number of target and effector cells.
  • CEM-ss were cultured with virus only.
  • the HIV isolates tested and their V3 sequences are listed in Table 2.
  • 0KT3/59.1 inhibited reverse transcriptase activity more than 95% in all cases in which the HIV isolate has the GPGRAF sequence (MN, Alabama, Duke 6587- 5, III B , SF2, and WMJ2; panels A, B, D, F, G, and H respectively) .
  • Two isolates, Duke 6587-7 (panel E) and Duke 7887-7 (panel C) having a GPGRAI motif were tested, and one (Duke 6587-7) was inhibited.
  • a mixture of unconjugated OKT3 and 59.1 (filled triangles) had no effect.
  • OKT3/6C5 Heteroconiugate Inhibits Reverse Transcriptase Activity of Infected Cells
  • OKT3/6C5 heteroconjugate was tested for its ability to inhibit reverse transcriptase activity of HIV- IIIB infected CEM-ss. Briefly, CEM-ss (15,000/well in a 96 well plate) were exposed to 64 IU of HIV-III B . After 18 hrs., CTL (45,000/well) and OKT3/6C5 heteroconjugate at various concentrations were added. Reverse transcriptase activity was measured 7 days later as described above. Referring to Fig. 6, OKT3/6C5 heteroconjugate (open circles) essentially eliminated reverse transcriptase activity at concentrations as low as 0.5 ng/ml. In contrast, a mixture unconjugated OKT3 and 6C5 had no significant effect on reverse transcriptase activity.
  • OKT3/59.1 and OKT3/6C5 Are Cytotoxic in the Presence of C£L
  • OKT3/59.1 heteroconjugate at 10 ⁇ g/ml lysed 58% of the VPE16 infected CV1 cells and 62% of the VMN infected CVl cells. Lyses of uninfected cells was very low. Cell lyses was similarly low when mono eric antibodies were added (data not shown) . That the maximum lysis using OKT3/59.1 was 60% as opposed to 100% is probably the result of incomplete infection of CVl cells by the vaccinia virus (Syncytia formation assays with limiting dilutions of CVl cells indicated that approximately 50-60% of the cells expressing gpl60) .
  • the assay described below is used to determine the potency of the heteroconjugate antibodies of the invention. By using a variety of HIV strains the breadth of reactivity of a given heteroconjugate antibody may also be determined. In order to accurately determine the potency of the heteroconjugate antibodies of the invention it is important to measure the effect of the heteroconjugate antibody on HIV infected cells under carefully controlled conditions.
  • the preferred assay is described below. CEM-ss cells (150,000 cells/well in 24 well microtiter plates, 2 ml wells) are infected with 100- 1000 infectious units (IU) of the desired HIV strain.
  • reverse transcriptase activity should not be measured at 10 days post-infection. Instead the reverse transcriptase activity should be measured at a time which is close to that of maximum virus production.
  • the infectious units are determined according to the Karber method. Because viral titer can decrease during storage, it is important that the viral stock be freshly titered. Viral stocks should be carefully prepared so that the number of defective viral particles is low. For example, the multiplicity of infection for preparing viral stocks should be 0.001, cells should be grown under conditions which allow logarithmic cell growth, and virus should be collected at the peak of virus production (as determined by maximal reverse transcriptase activity or p24 expression) . Engineered Heteroconiugate Antibodies Since, for the most part, monoclonal antibodies are produced in species other than humans, they are often immunogenic to humans.
  • variable region the antigen binding portion
  • constant region the portion involved with providing structural stability and other biological functions
  • Quadromas can be used to generate bispecific antibodies (Reading et al. , U.S Patent Nos. 4,474,893 and 4,714,681) .
  • the antibody of the invention is administered parenterally, either via the intravenous or intramuscular route.
  • a typical treatment regimen would comprise administration of an effective amount of antibody administered over between about one week and about 6 months.
  • the number of treatments required to control a patient's disease may vary from individual to individual, depending upon the severity and stage of the illness and the individual characteristics of each patient being treated.
  • the total dose required for each treatment may be administered by multiple doses or in a single dose.
  • the human monoclonal antibody may be administered alone or in conjunction with other HIV treatments, such as AZT, in order to control a patient's disease.
  • Pharmaceutical compositions of heteroconjugate antibodies are produced according to the intended mode of administration and may include: liposomes, solutions, suspensions and microparticles.
  • peripheral blood lymphocytes may be collected from an individual in need of treatment for HIV infection (or a compatible donor) and incubated with a heteroconjugate antibody prior to reinfusion of the cells.
  • the PBL may be expanded in culture (Rosenberg et al. , Science 233:1318, 1986).
  • the PBL may also be incubated with interieukins, interferons, or other immunomodulators.
  • the cells may be incubated with molecules such as receptor specific antibodies which will stimulate the cytolytic activity of the effector cells (Scott et al.. Cellular Immunology 114:370, 1988).

Abstract

L'invention se rapporte à un anticorps d'hétéroconjugués qui contient deux fonctions de liaison. La première fonction de liaison est dirigée contre un antigène de cellules effectrices du sang périphérique, tel que de préférence l'antigène CD-3. La seconde fonction est dirigée contre un domaine spécifique d'une protéine recouvrant le virus du SIDA, tel que de préférence la séquence de boucles V3 de la protéine d'enveloppe gp120, provenant de l'HIV MN ou d'une variante de celui-ci. Sont également décrits des procédés thérapeutiques, dans lesquels 20 ng/ml d'une culture mélangée de cellules infectées par l'HIV (cellules effectrices et cellules CEM-ss) produisent une diminution de 80 à 90 % de l'activité de la transcriptase inverse par rapport à une culture identique ayant un rapport cellules effectrices/cellules CEM-ss égal à 3/1.
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CA2102511A1 (fr) 1992-11-15
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