WO2011072124A1 - Delivery system for cytotoxic drugs by bispecific antibody pretargeting - Google Patents
Delivery system for cytotoxic drugs by bispecific antibody pretargeting Download PDFInfo
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- WO2011072124A1 WO2011072124A1 PCT/US2010/059686 US2010059686W WO2011072124A1 WO 2011072124 A1 WO2011072124 A1 WO 2011072124A1 US 2010059686 W US2010059686 W US 2010059686W WO 2011072124 A1 WO2011072124 A1 WO 2011072124A1
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
Definitions
- the present invention relates to therapeutic conjugates with improved ability to target diseases, such as cancer, infectious disease, autoimmune disease, immune dysfunction (e.g., graft versus host disease, organ transplant rejection), cardiovascular disease, metabolic disease and neurologic (e.g., neurodegenerative) disease.
- the delivery system comprises a pretargeting method in which bispecific antibodies have one or more binding sites for a disease associated antigen and one or more binding sites for a hapten on a targetable construct.
- the targetable construct may comprise therapeutic agents, such as cytotoxic drugs, and/or diagnostic agents, such as radionuclides. More preferably, the cytotoxic drug may be SN-38.
- the bispecific antibody is made by the dock- and-lock (DNL) technique.
- Monoclonal antibodies have been used for the targeted delivery of toxic agents to cancer and other diseased cells.
- immunoconjugates of antibodies and toxic agents have had mixed success in the therapy of cancer or autoimmune disease, and little application in other diseases, such as infectious disease.
- the toxic agent is most commonly a
- Irinotecan also referred to as CPT-1 1
- topotecan are CPT analogs that are approved cancer therapeutics (Iyer and Ratain, 1998, Cancer Chemother Phamacol 42:S31 -S43). CPTs act by inhibiting topoisomerase I (Hsiang et al., 1985, J Biol Chem 260: 14873-78).
- potent cytotoxic agents therapeutic use of camptothecins is limited by its relative insolubility in aqueous solution and high systemic toxicity, which limits the effective dosage that may be delivered to targeted disease cells. A need exists in the field for more effective targeted delivery methods for camptothecins and other therapeutic agents.
- the present invention resolves an unfulfilled need in the art by providing improved methods and compositions for targeted delivery of therapeutic agents.
- the methods and compositions comprise pretargeting with novel bispecific antibody constructs, which contain at least one binding site for a disease associated antigen, such as a tumor-associated antigen, a B-cell associated antigen, or a pathogen-associated antigen, and at least one binding site for a hapten on a targetable construct.
- a disease associated antigen such as a tumor-associated antigen, a B-cell associated antigen, or a pathogen-associated antigen
- the targetable construct serves as a carrier for therapeutic or diagnostic agents.
- the bispecific antibody constructs are prepared by the dock-and-lock (DNL) teclinique (see, e.g., U.S. Patent Nos. 7,550,143; 7,521 ,056; 7,534,866; 7,527,787 and 7,666,400, the Examples section of each incorporated herein by reference).
- the DNL technique utilizes the specific binding interactions occurring between a dimerization and docking domain (DDD moiety) from protein kinase A, and an anchoring domain (AD moiety) from any of a number of known A-kinase anchoring proteins (AKAPs).
- DDD moieties spontaneously form dimers which then bind to an AD moiety.
- An antibody or antigen-binding fragment of use may be chimeric, humanized or human.
- the use of chimeric antibodies is preferred to the parent murine antibodies because they possess human antibody constant region sequences and therefore do not elicit as strong a human anti-mouse antibody (HAMA) response as murine antibodies.
- HAMA human anti-mouse antibody
- the use of humanized antibodies is even more preferred, in order to further reduce the possibility of inducing a HAMA reaction.
- techniques for humanization of murine antibodies by replacing murine framework and constant region sequences with corresponding human antibody framework and constant region sequences are well known in the art and have been applied to numerous murine anti-cancer antibodies.
- Antibody humanization may also involve the substitution of one or more human framework amino acid residues with the corresponding residues from the parent murine framework region sequences.
- techniques for production of human antibodies are also well known.
- granulomatosis membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, psoriasis, or fibrosing alveolitis.
- the therapeutic agent is a cytotoxic agent, such as a drug or a toxin.
- the drug is selected from the group consisting of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, gemcitabine, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antibiotics, enzyme inhibitors, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, hormone antagonists, endostatin, taxols, camptothecins, SN-38, doxorubicins and their analogs, antimetabolites, alkylating agents, antimitotics, anti-angiogenic agents, tyrosine kinase inhibitors, mTOR inhibitor
- Such radionuclides include, but are not limited to: Dy-152, At-21 1 , Bi-212, Ra- 223, Rn-219, Po-215, Bi-211, Ac-225, Fr-221 , At-217, Bi-213 and Fm-255. Decay energies of useful alpha-particle-emitting radionuclides are preferably 2,000-10,000 keV, more preferably 3,000-8,000 keV, and most preferably 4,000-7,000 keV.
- radioisotopes of use include n C, 13 N, 15 0, 75 Br, 198 Au, 224 Ac, 126 I, 133 I, 77 Br, 1 13m
- the therapeutic agent is a photoactive therapeutic agent selected from the group consisting of chromogens and dyes.
- the therapeutic agent is an enzyme selected from the group consisting of malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta- galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase.
- malate dehydrogenase staphylococcal nuclease
- delta-V-steroid isomerase yeast alcohol dehydrogenase
- alpha-glycerophosphate dehydrogenase alpha-glycerophosphate dehydrogenase
- triose phosphate isomerase horseradish peroxidas
- Camptothecin (CPT) and its analogs and derivatives are preferred chemotherapeutic moieties, although the invention is not so limited.
- Other chemotherapeutic moieties that are within the scope of the invention are taxanes (e.g, baccatin III, taxol), calicheamicin, epothilones, anthracycline drugs (e.g., doxorubicin (DOX), epirubicin,
- morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin
- the drug conjugates may be used in combination with surgery, radiation therapy, chemotherapy, immunotherapy with naked antibodies, radioimmunotherapy, immunomodulators, vaccines, and the like. Similar combinations are preferred in the treatment of other diseases amenable to targeting moieties, such as autoimmune diseases.
- camptothecin conjugates can be combined with TNF inhibitors, B-cell antibodies, interferons, interleukins, and other effective agents for the treatment of autoimmune diseases, such as rheumatoid arthritis, systemic lupus
- Antibodies and antigen-based vaccines against these and other viral pathogens are known in the art and, in some cases, already in commercial use.
- An antibody refers to a full-length (i.e., naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes)
- a chimeric antibody is a recombinant protein that contains the variable domains including the complementarity determining regions (CDRs) of an antibody derived from one species, preferably a rodent antibody, while the constant domains of the antibody molecule are derived from those of a human antibody.
- the constant domains of the chimeric antibody may be derived from that of other species, such as a cat or dog.
- a human antibody is, e.g., an antibody obtained from transgenic mice that have been "engineered” to produce specific human antibodies in response to antigenic challenge.
- elements of the human heavy and light chain loci are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disruptions of the endogenous murine heavy chain and light chain loci.
- the transgenic mice can synthesize human antibodies specific for particular antigens, and the mice can be used to produce human antibody-secreting hybridomas.
- Methods for obtaining human antibodies from transgenic mice are described by Green et al., Nature Genet. 7: 13 (1994), Lonberg et al., Nature 368:856 (1994), and Taylor et al., Int. Immun.
- a therapeutic agent is a compound, molecule or atom which is administered separately, concurrently or sequentially with an antibody moiety or conjugated to an antibody moiety, i.e., antibody or antibody fragment, or a subfragment, and is useful in the treatment of a disease.
- therapeutic agents include antibodies, antibody fragments, drugs, toxins, nucleases, hormones, immunomodulators, pro-apoptotic agents, anti-angiogenic agents, boron compounds, photoactive agents or dyes and radioisotopes. Therapeutic agents of use are described in more detail below.
- An immunoconjugate is an antibody, antibody fragment or fusion protein conjugated to at least one therapeutic and/or diagnostic agent.
- CPT is abbreviation for camptothecin, and as used in the present application CPT represents camptothecin itself or an analog or derivative of camptothecin.
- CPT represents camptothecin itself or an analog or derivative of camptothecin.
- the chemotherapeutic moiety is selected from the group consisting of doxorubicin (DOX), epirubicin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2- PDOX), CPT, 10-hydroxy camptothecin, SN-38, topotecan, lurtotecan, 9- aminocamptothecin, 9-nitrocamptothecin, taxanes, geldanamycin, ansamycins, and epothilones.
- the chemotherapeutic moiety is SN-38.
- the moiety labeled with one or more diagnostic and/or therapeutic agents may comprise a peptide or other targetable construct.
- Labeled peptides (or proteins) may be selected to bind directly to a targeted cell, tissue, pathogenic organism or other target.
- labeled peptides may be selected to bind indirectly, for example using a bispecific antibody with one or more binding sites for a targetable construct peptide and one or more binding sites for a target antigen associated with a disease or condition.
- Bispecific antibodies may be used, for example, in a pretargeting technique wherein the antibody may be administered first to a subject.
- a targetable construct such as a labeled peptide, may be administered to the subject and allowed to bind to the bispecific antibody and localize at the diseased cell or tissue.
- targetable constructs can be of diverse structure and are selected not only for the availability of an antibody or fragment that binds with high affinity to the targetable construct, but also for rapid in vivo clearance when used within the pre-targeting method and bispecific antibodies or multispecific antibodies. Hydrophobic agents are best at eliciting strong immune responses, whereas hydrophilic agents are preferred for rapid in vivo clearance. Thus, a balance between hydrophobic and hydrophilic character is established. This may be accomplished, in part, by using hydrophilic chelating agents to offset the inherent hydrophobicity of many organic moieties. Also, subunits of the targetable construct may be chosen which have opposite solution properties, for example, peptides, which contain amino acids, some of which are hydrophobic and some of which are hydrophilic. Aside from peptides, carbohydrates may also be used.
- Peptides having as few as two amino acid residues, preferably two to ten residues, may be used and may also be coupled to other moieties, such as chelating agents.
- the linker should be a low molecular weight conjugate, preferably having a molecular weight of less than 50,000 daltons, and advantageously less than about 20,000 daltons, 10,000 daltons or 5,000 daltons.
- the targetable construct peptide will have four or more residues, such as the peptide DOTA-Phe-Lys(HSG)-Tyr-Lys(HSG)-NH 2 (SEQ ID NO:81), wherein DOTA is 1,4,7,10-tetraazacyclododecane1,4,7,10-tetraacetic acid and HSG is the histamine succinyl glycyl group.
- DOTA may be replaced by NOTA (1,4,7-triaza- cyclononane-l ,4,7-triacetic acid), TETA (p-bromoacetamido-benzyl- tetraethylaminetetraacetic acid), NETA ([2-(4,7-biscarboxymethyl[l ,4,7]triazacyclononan-l - yl-ethyl]-2-carbonylmethyl-amino]acetic acid), DTPA or other known chelating moieties.
- the targetable construct may also comprise unnatural amino acids, e.g., D-amino acids, in the backbone structure to increase the stability of the peptide in vivo. In alternative embodiments, other backbone structures such as those constructed from non-natural amino acids or peptoids may be used.
- the peptides used as targetable constructs are conveniently synthesized on an automated peptide synthesizer using a solid-phase support and standard techniques of repetitive orthogonal deprotection and coupling. Free amino groups in the peptide, that are to be used later for conjugation of chelating moieties or other agents, are advantageously blocked with standard protecting groups such as a Boc group, while N-terminal residues may be acetylated to increase serum stability.
- protecting groups are well known to the skilled artisan. See Greene and Wuts Protective Groups in Organic Synthesis, 1999 (John Wiley and Sons, N.Y.).
- the peptides are prepared for later use within the bispecific antibody system, they are advantageously cleaved from the resins to generate the corresponding C- terminal amides, in order to inhibit in vivo carboxypeptidase activity.
- Exemplary methods of peptide synthesis are disclosed in the Examples below.
- the antibody will contain a first binding site for an antigen produced by or associated with a target tissue and a second binding site for a hapten on the targetable construct.
- haptens include, but are not limited to, HSG and In-DTPA.
- Antibodies raised to the HSG hapten are known (e.g. 679 antibody) and can be easily incorporated into the appropriate bispecific antibody (see, e.g., U.S. Patent Nos. 6,962,702; 7,138,103 and 7,300,644, incorporated herein by reference with respect to the Examples sections).
- haptens and antibodies that bind to them are known in the art and may be used, such as In-DTPA and the 734 antibody (e.g., U.S. Patent No.7, 534,431 , the Examples section incorporated herein by reference).
- the specificity of the click chemistry reaction may be used as a substitute for the antibody-hapten binding interaction used in pretargeting with bispecific antibodies.
- the specific reactivity of e.g., cyclooctyne moieties for azide moieties or alkyne moieties for nitrone moieties may be used in an in vivo cycloaddition reaction.
- An antibody or other targeting molecule is activated by incorporation of a substituted cyclooctyne, an azide or a nitrone moiety.
- a targetable construct is labeled with one or more diagnostic or therapeutic agents and a complementary reactive moiety.
- the targeting molecule comprises a cyclooctyne
- the targetable construct will comprise an azide
- the targeting molecule comprises a nitrone
- the targetable construct will comprise an alkyne, etc.
- the activated targeting molecule is administered to a subject and allowed to localize to a targeted cell, tissue or pathogen, as disclosed for pretargeting protocols.
- the reactive labeled targetable construct is then administered. Because the cyclooctyne, nitrone or azide on the targetable construct is unreactive with endogenous biomolecules and highly reactive with the complementary moiety on the targeting molecule, the specificity of the binding interaction results in the highly specific binding of the targetable construct to the tissue-localized targeting molecule.
- targetable constructs are peptides
- polymeric molecules such as polyethylene glycol (PEG)
- PEG polyethylene glycol
- the labeled polymer may be utilized for delivery of diagnostic or therapeutic agents.
- PEG polyethylene glycol
- carrier molecules include but not limited to polymers, nanoparticles, microspheres, liposomes and micelles.
- Targeting antibodies of use may be specific to or selective for a variety of cell surface or disease-associated antigens.
- Exemplary target antigens of use for imaging or treating various diseases, conditions, syndromes or disorders such as a malignant disease, a cardiovascular disease, an infectious disease, an inflammatory disease, an autoimmune disease, a metabolic (e.g., endocrine) disease, or a neurological (e.g., neurodegenerative) disease, such as Alzheimer's, may include carbonic anhydrase IX, CCCL19, CCCL21, CSAp, CD1 , CDla, CD2, CD3, CD4, CD5, CD8, CD1 1A, CD14, CD15, CD16, CD18, CD19, IGF- 1R, CD20, CD21 , CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e,
- Tumor-associated markers have been categorized by Herberman, supra, in a number of categories including oncofetal antigens, placental antigens, oncogenic or tumor virus associated antigens, tissue associated antigens, organ associated antigens, ectopic hormones and normal antigens or variants thereof. Occasionally, a sub-unit of a tumor-associated marker is advantageously used to raise antibodies having higher tumor-specificity, e.g., the beta-subunit of human chorionic gonadotropin (HCG) or the gamma region of HCG.
- HCG human chorionic gonadotropin
- CEA carcinoembryonic antigen
- MAbs can be isolated and purified from hybridoma cultures by a variety of well-established techniques. Such isolation techniques include affinity chromatography with Protein-A or Protein-G Sepharose, size-exclusion chromatography, and ion-exchange chromatography. See, for example, Coligan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3. Also, see Baines et al , "Purification of Immunoglobulin G (IgG)," in METHODS IN
- a chimeric antibody is a recombinant protein in which the variable regions of a human antibody have been replaced by the variable regions of, for example, a mouse antibody, including the complementarity-determining regions (CDRs) of the mouse antibody.
- Chimeric antibodies exhibit decreased immunogenicity and increased stability when administered to a subject.
- CDRs complementarity-determining regions
- variable domains of a human antibody The mouse framework regions (FR) in the chimeric monoclonal antibody are also replaced with human FR sequences.
- additional modification might be required in order to restore the original affinity of the murine antibody. This can be accomplished by the replacement of one or more human residues in the FR regions with their murine counterparts to obtain an antibody that possesses good binding affinity to its epitope. See, for example, Tempest et al., Biotechnology 9:266 (1991) and Verhoeyen et al, Science 239: 1534 (1988).
- Preferred residues for substitution include FR residues that are located within 1 , 2, or 3 Angstroms of a CDR residue side chain, that are located adjacent to a CDR sequence, or that are predicted to interact with a CDR residue.
- the phage display technique may be used to generate human antibodies (e.g., Dantas-Barbosa et al, 2005, Genet. Mol. Res. 4: 126-40).
- Human antibodies may be generated from normal humans or from humans that exhibit a particular disease state, such as cancer (Dantas-Barbosa et al., 2005).
- the advantage to constructing human antibodies from a diseased individual is that the circulating antibody repertoire may be biased towards antibodies against disease-associated antigens.
- Fab fragment antigen binding protein
- RNAs were converted to cDNAs and used to make Fab cDNA libraries using specific primers against the heavy and light chain immunoglobulin sequences (Marks et al., 1991 , J Mol. Biol. 222:581-97).
- Library construction was performed according to Andris-Widhopf et al. (2000, In: Phage Display Laboratory Manual, Barbas et al. (eds), 1 st edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY pp. 9.1 to 9.22).
- Fab fragments were digested with restriction endonucleases and inserted into the bacteriophage genome to make the phage display library.
- libraries may be screened by standard phage display methods, as known in the art.
- Phage display can be performed in a variety of formats, for their review, see e.g. Johnson and Chiswell, Current Opinion in Structural Biology 3:5564-571 (1993).
- the XenoMouse® was transformed with germline-configured YACs (yeast artificial chromosomes) that contained portions of the human IgH and Igkappa loci, including the majority of the variable region sequences, along with accessory genes and regulatory sequences.
- the human variable region repertoire may be used to generate antibody producing B-cells, which may be processed into hybridomas by known techniques.
- a XenoMouse® immunized with a target antigen will produce human antibodies by the normal immune response, which may be harvested and/or produced by standard techniques discussed above.
- a variety of strains of XenoMouse® are available, each of which is capable of producing a different class of antibody.
- Transgenically produced human antibodies have been shown to have therapeutic potential, while retaining the pharmacokinetic properties of normal human antibodies (Green et al, 1999).
- the skilled artisan will realize that the claimed compositions and methods are not limited to use of the XenoMouse® system but may utilize any transgenic animal that has been genetically engineered to produce human antibodies.
- the targeting molecules of use may incorporate any antibody or fragment known in the art that has binding specificity for a target antigen associated with a disease state or condition.
- known antibodies include, but are not limited to, hRl (anti-IGF-lR, U.S. Patent Application Serial No. 12/772,645, filed 3/12/10)
- hPAM4 anti-pancreatic cancer mucin, U.S. Patent No. 7,282,567), hA20 (anti-CD20, U.S. Patent No. 7,251 ,164), hA19 (anti-CD19, U.S. Patent No. 7,109,304), hIMMU31 (anti-AFP, U.S. Patent No.
- a pharmaceutical composition of the present invention may be used to treat a subject having a metabolic disease, such amyloidosis, or a neurodegenerative disease, such as Alzheimer's disease.
- a metabolic disease such as amyloidosis
- a neurodegenerative disease such as Alzheimer's disease.
- Bapineuzumab is in clinical trials for Alzheimer's disease therapy.
- Other antibodies proposed for therapy of Alzheimer's disease include Alz 50 (Ksiezak-Reding et al., 1987, J Biol Chem 263 :7943-47), gantenerumab, and solanezumab.
- Infliximab an anti-TNF-a antibody, has been reported to reduce amyloid plaques and improve cognition.
- compositions and methods include cardiovascular diseases, such as fibrin clots,
- Antibodies to fibrin e.g., scFv(59D8); T2Gl s; MHl
- scFv(59D8); T2Gl s; MHl are known and in clinical trials as imaging agents for disclosing said clots and pulmonary emboli
- anti-granulocyte antibodies such as MN-3, MN-15, anti-NCA95, and anti-CD 15 antibodies, can target myocardial infarcts and myocardial ischemia.
- Abciximab (anti-glycoprotein Ilb/IIIa) has been approved for adjuvant use for prevention of restenosis in percutaneous coronary interventions and the treatment of unstable angina (Waldmann et al., 2000, Hematol 1 :394-408).
- Anti-CD3 antibodies have been reported to reduce development and progression of atherosclerosis (Steffens et al., 2006, Circulation 1 14: 1977-84).
- Antibodies against oxidized LDL induced a regression of established atherosclerosis in a mouse model (Ginsberg, 2007, J Am Coll Cardiol 52:2319-21).
- Anti- ICAM-1 antibody was shown to reduce ischemic cell damage after cerebral artery occlusion in rats (Zhang et al, 1994, Neurology 44: 1747-51).
- Commercially available monoclonal antibodies to leukocyte antigens are represented by: OKT anti-T-cell monoclonal antibodies (available from Ortho Pharmaceutical Company) which bind to normal T-lymphocytes; the monoclonal antibodies produced by the hybridomas having the ATCC accession numbers HB44, HB55, HB12, HB78 and HB2; G7E11, W8E7, NKP15 and G022 (Becton Dickinson); NEN9.4 (New England Nuclear); and FMC11 (Sera Labs). A description of antibodies against fibrin and platelet antigens is contained in Knight, Semin. Nucl. Med., 20:52-67 (1990).
- Such known antibodies are of use for detection and/or treating a variety of disease states or conditions (e.g., hMN-14 or TF2 (CEA- expressing carcinomas), hA20 or TF-4 (lymphoma), hPAM4 or TF-10 (pancreatic cancer), RS7 (lung, breast, ovarian, prostatic cancers), hMN-15 or hMN3 (inflammation), anti-gpl20 and/or anti-gp41 (HIV), anti-platelet and anti-thrombin (blood clots), anti-myosin (cardiac necrosis), anti-CXCR4 (cancer and inflammatory disease)).
- hMN-14 or TF2 CEA- expressing carcinomas
- hA20 or TF-4 lymphoma
- hPAM4 or TF-10 pancreatic cancer
- RS7 lung, breast, ovarian, prostatic cancers
- hMN-15 or hMN3 inflammation
- antibody sequences or antibody- secreting hybridomas against almost any disease-associated antigen may be obtained by a simple search of the ATCC, NCBI and/or USPTO databases for antibodies against a selected disease-associated target of interest.
- the antigen binding domains of the cloned antibodies may be amplified, excised, ligated into an expression vector, transfected into an adapted host cell and used for protein production, using standard techniques well known in the art.
- Antibody fragments which recognize specific epitopes can be generated by known techniques.
- the antibody fragments are antigen binding portions of an antibody, such as F(ab') 2j Fab', F(ab) 2 , Fab, Fv, sFv and the like.
- F(ab') 2 fragments can be produced by pepsin digestion of the antibody molecule and Fab' fragments can be generated by reducing disulfide bridges of the F(ab') 2 fragments.
- Fab ' expression libraries can be constructed (Huse et al , 1989, Science, 246: 1274-1281) to allow rapid and easy identification of monoclonal Fab' fragments with the desired specificity.
- An scFv library with a large repertoire can be constructed by isolating V-genes from non-immunized human donors using PCR primers corresponding to all known VH, V kappa and V 80 gene families. See, e.g., Vaughn et al., Nat. Biotechnol., 14: 309-314 (1996). Following amplification, the V kappa and V lambda pools are combined to form one pool. These fragments are ligated into a phagemid vector. The scFv linker is then ligated into the phagemid upstream of the VL fragment. The VH and linker-V L fragments are amplified and assembled on the JH region. The resulting VH -linker-V L fragments are ligated into a phagemid vector. The phagemid library can be panned for binding to the selected antigen.
- VHH Single domain antibodies
- Single domain antibodies may be obtained, for example, from camels, alpacas or llamas by standard immunization techniques.
- the VHH may have potent antigen-binding capacity and can interact with novel epitopes that are inaccessible to conventional VH-VL pairs.
- Alpaca serum IgG contains about 50% camelid heavy chain only IgG antibodies (Cabs) (Maass et al, 2007).
- Alpacas may be immunized with known antigens and VHHs can be isolated that bind to and neutralize the target antigen (Maass et al., 2007).
- PCR primers that amplify virtually all alpaca VHH coding sequences have been identified and may be used to construct alpaca VHH phage display libraries, which can be used for antibody fragment isolation by standard biopanning techniques well known in the art (Maass et al., 2007). These and other known antigen-binding antibody fragments may be utilized in the claimed methods and compositions.
- VK variable light chain
- V H variable heavy chain sequences for an antibody of interest
- the V genes of a MAb from a cell that expresses a murine MAb can be cloned by PCR amplification and sequenced.
- the cloned VL and VH genes can be expressed in cell culture as a chimeric Ab as described by Orlandi et al. , (Proc. Natl.
- a humanized MAb can then be designed and constructed as described by Leung et al. (Mol Immunol , 32: 1413 (1995)).
- cDNA can be prepared from any known hybridoma line or transfected cell line producing a murine MAb by general molecular cloning techniques (Sambrook et al., Molecular Cloning, A laboratory manual, 2 nd Ed (1989)).
- the VK sequence for the MAb may be amplified using the primers VKIBACK and VKIFOR (Orlandi et al, 1989) or the extended primer set described by Leung et al. (BioTechniques, 15: 286 (1993)).
- VH sequences can be amplified using the primer pair VHIBACK/VHIFOR (Orlandi et al, 1989) or the primers annealing to the constant region of murine IgG described by Leung et al. (Hybridoma, 13:469 (1994)).
- Humanized V genes can be constructed by a combination of long oligonucleotide template syntheses and PCR amplification as described by Leung et al. (Mol. Immunol, 32: 1413 (1995)).
- the expression vectors can be co-transfected into an appropriate cell and supernatant fluids monitored for production of a chimeric, humanized or human MAb.
- the VK and VH expression cassettes can be excised and subcloned into a single expression vector, such as pdHL2, as described by Gillies et al. (J Immunol. Methods 125:191 (1989) and also shown in Losman et al, Cancer, 80:2660 (1997)).
- expression vectors may be transfected into host cells that have been pre-adapted for transfection, growth and expression in serum-free medium.
- Exemplary cell lines that may be used include the Sp/EEE, Sp/ESF and Sp/ESF-X cell lines (see, e.g., U.S. Patent Nos. 7,531,327; 7,537,930 and 7,608,425; the Examples section of each of which is incorporated herein by reference). These exemplary cell lines are based on the Sp2/0 myeloma cell line, transfected with a mutant Bcl-EEE gene, exposed to methotrexate to amplify transfected gene sequences and pre-adapted to serum-free cell line for protein expression.
- PKA which plays a central role in one of the best studied signal transduction pathways triggered by the binding of the second messenger cAMP to the R subunits
- the structure of the holoenzyme consists of two catalytic subunits held in an inactive form by the R subunits (Taylor, J. Biol. Chem. 1989;264:8443). Isozymes of PKA are found with two types of R subunits (RI and RII), and each type has a and ⁇ isoforms (Scott, Pharmacol. Ther.
- the amino acid sequences of the AD are quite varied among individual AKAPs, with the binding affinities reported for RII dimers ranging from 2 to 90 nM (Alto et al, Proc. Natl. Acad. Sci. USA. 2003;100:4445). AKAPs will only bind to dimeric R subunits.
- the AD binds to a hydrophobic surface formed by the 23 amino-terminal residues (Colledge and Scott, Trends Cell Biol. 1999; 6:216).
- the dimerization domain and AKAP binding domain of human Rlla are both located within the same N-terminal 44 amino acid sequence (Newlon et al, Nat. Struct. Biol. 1999;6:222; Newlon et ah, EMBO J. 2001 ;20: 1651), which is termed the DDD herein.
- Entity B is constructed by linking an AD sequence to a precursor of B, resulting in a second component hereafter referred to as b.
- the dimeric motif of DDD contained in a 2 will create a docking site for binding to the AD sequence contained in b, thus facilitating a ready association of a 2 and b to form a binary, trimeric complex composed of a 2 b.
- site of attachment of an AD or DDD moiety to an effector moiety may vary, depending on the chemical nature of the effector moiety and the part(s) of the effector moiety involved in its physiological activity.
- Site-specific attachment of a variety of effector moieties may be performed using techniques known in the art, such as the use of bivalent cross-linking reagents and/or other chemical conjugation techniques.
- click chemistry reactions may be used to produce an AD or DDD peptide conjugated to an effector moiety, or even to covalently attach the AD and DDD moiety to each other to provide an irreversible covalent bond to stabilize the DNL complex.
- a pre-targeting method of treating or diagnosing a disease or disorder in a subject may be provided by: (1) administering to the subject a bispecific antibody or antibody fragment; (2) optionally administering to the subject a clearing composition, and allowing the composition to clear the antibody from circulation; and (3) administering to the subject the targetable construct, containing one or more chelated or chemically bound therapeutic or diagnostic agents.
- MONOCLONAL ANTIBODIES PRODUCTION, ENGINEERING AND CLINICAL APPLICATION, Ritter et al. (eds.), pages 60-84 (Cambridge University Press 1995).
- the carrier moiety can be conjugated via a carbohydrate moiety in the Fc region of the antibody.
- the Fc region may be absent if the antibody component of the immunoconjugate is an antibody fragment. However, it is possible to introduce a carbohydrate moiety into the light chain variable region of a full length antibody or antibody fragment. See, for example, Leung et al, J. Immunol. 154: 5919 (1995); U.S. Patent Nos. 5,443,953 and 6,254,868, the
- the engineered carbohydrate moiety is used to attach the therapeutic or diagnostic agent.
- the azide alkyne Huisgen cycloaddition reaction uses a copper catalyst in the presence of a reducing agent to catalyze the reaction of a terminal alkyne group attached to a first molecule.
- a second molecule comprising an azide moiety
- the azide reacts with the activated alkyne to form a 1 ,4-disubstituted 1 ,2,3-triazole.
- the copper catalyzed reaction occurs at room temperature and is sufficiently specific that purification of the reaction product is often not required.
- cyclooctyne is an 8-carbon ring structure comprising an internal alkyne bond.
- the closed ring structure induces a substantial bond angle deformation of the acetylene, which is highly reactive with azide groups to form a triazole.
- cyclooctyne derivatives may be used for copper- free click reactions (Id.)
- Agard et al. (2004, J Am Chem Soc 126: 15046-47) demonstrated that a recombinant glycoprotein expressed in CHO cells in the presence of peracetylated N- azidoacetylmannosamine resulted in the bioincorporation of the corresponding N-azidoacetyl sialic acid in the carbohydrates of the glycoprotein.
- the azido-derivatized glycoprotein reacted specifically with a biotinylated cyclooctyne to form a biotinylated glycoprotein, while control glycoprotein without the azido moiety remained unlabeled (Id.) Laughlin et al.
- the TCO-labeled CC49 antibody was administered to mice bearing colon cancer xenografts, followed 1 day later by injection of 1 1 'in-labeled tetrazine probe (Id.)
- the reaction of radiolabeled probe with tumor localized antibody resulted in pronounced radioactivity localization in the tumor, as demonstrated by SPECT imaging of live mice three hours after injection of radiolabeled probe, with a tumor- to-muscle ratio of 13: 1 (Id.)
- the results confirmed the in vivo chemical reaction of the TCO and tetrazine-labeled molecules.
- the landscaped antibodies were subsequently reacted with agents comprising a ketone-reactive moiety, such as hydrazide, hydrazine, hydroxylamino or thiosemicarbazide groups, to form a labeled targeting molecule.
- agents attached to the landscaped antibodies included chelating agents like DTP A, large drug molecules such as doxorubicin-dextran, and acyl-hydrazide containing peptides.
- the landscaping technique is not limited to producing antibodies comprising ketone moieties, but may be used instead to introduce a click chemistry reactive group, such as a nitrone, an azide or a cyclooctyne, onto an antibody or other biological molecule.
- Reactive targeting molecule may be formed either by either chemical conjugation or by biological incorporation.
- the targeting molecule such as an antibody or antibody fragment, may be activated with an azido moiety, a substituted cyclooctyne or alkyne group, or a nitrone moiety.
- the targeting molecule comprises an azido or nitrone group
- the corresponding targetable construct will comprise a substituted cyclooctyne or alkyne group, and vice versa.
- Such activated molecules may be made by metabolic incorporation in living cells, as discussed above. Alternatively, methods of chemical conjugation of such moieties to biomolecules are well known in the art, and any such known method may be utilized.
- the targeting molecules or targetable constructs disclosed herein may be attached to one or more therapeutic and/or diagnostic agents.
- Therapeutic agent are preferably selected from the group consisting of a radionuclide, an immunomodulator, an anti- angiogenic agent, a cytokine, a chemokine, a growth factor, a hormone, a drug, a prodrug, an enzyme, an oligonucleotide, a pro-apoptotic agent, an interference RNA, a photoactive therapeutic agent, a cytotoxic agent, which may be a chemotherapeutic agent or a toxin, and a combination thereof.
- the drugs of use may possess a pharmaceutical property selected from the group consisting of antimitotic, antikinase, alkylating, antimetabolite, antibiotic, alkaloid, anti- angiogenic, pro-apoptotic agents and combinations thereof.
- Exemplary drugs of use include, but are not limited to, 5-fluorouracil, aplidin, azaribine, anastrozole, anthracyclines, bendamustine, bleomycin, bortezomib, bryostatin- 1 , busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, Celebrex, chlorambucil, cisplatin (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirub
- Toxins of use may include ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), e.g., onconase, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.
- RNase ribonuclease
- interferons-a, - ⁇ or - ⁇ interferons-a, - ⁇ or - ⁇ , and stem cell growth factor, such as that designated "SI factor”.
- cytokines include growth hormones such as human growth hormone, N- methionyl human growth hormone, and bovine growth hormone; parathyroid hormone;
- integrin thrombopoietin
- nerve growth factors such as NGF-B; platelet-growth factor; transforming growth factors (TGFs) such as TGF- a and TGF- B; insulin-like growth factor-I and -II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon-a, - ⁇ , and - ⁇ ; colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); interleukins (ILs) such as IL- 1 , IL- 1 a, IL-2, IL-3 , IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL- 10, IL- 1 1 , IL- 12; IL- 13 , IL-14, IL-15, IL-16, IL-17, IL-18, IL-21 , IL-25, LIF, kit-ligand or FLT-3, angiostatin,
- Radioactive isotopes useful for treating diseased tissue include, but are not limited to- m In, 177 Lu, 212 Bi, 213 Bi, 2U At, 62 Cu, 67 Cu, 90 Y, 125 I, 131 1, 32 P, 33 P, 47 Sc, n l Ag, 67 Ga, 142 Pr, 153 Sm, 161 Tb, 166 Dy, 166 Ho, 186 Re, 188 Re, 189 Re, 212 Pb, 223 Ra, 225 Ac, 59 Fe, 75 Se, 77 As, 89 Sr, 99 Mo, 105 Rh, 109 Pd, ,43 Pr, 149 Pm, 169 Er, 194 Ir, 198 Au, 199 Au, and 211 Pb.
- the therapeutic radionuclide preferably has a decay-energy in the range of 20 to 6,000 keV, preferably in the ranges 60 to 200 keV for an Auger emitter, 100-2,500 keV for a beta emitter, and 4,000-6,000 keV for an alpha emitter.
- Maximum decay energies of useful beta- particle-emitting nuclides are preferably 20-5,000 keV, more preferably 100-4,000 keV, and most preferably 500-2,500 keV. Also preferred are radionuclides that substantially decay with Auger-emitting particles.
- beta- particle-emitting nuclides are preferably ⁇ 1,000 keV, more preferably ⁇ 100 keV, and most preferably ⁇ 70 keV. Also preferred are radionuclides that substantially decay with generation of alpha-particles.
- Such radionuclides include, but are not limited to: Dy-152, At-21 1, Bi- 212, Ra-223, Rn-219, Po-215, Bi-21 1, Ac-225, Fr-221, At-217, Bi-213 and Fm-255. Decay energies of useful alpha-particle-emitting radionuclides are preferably 2,000-10,000 keV, more preferably 3,000-8,000 keV, and most preferably 4,000-7,000 keV.
- Additional potential radioisotopes of use include H C, 13 N, 15 0, 75 Br, 198 Au, 224 Ac, 126 I, 133 I, 77 Br, 1 13m In, 95 Ru, 97 Ru, 103 Ru, 105 Ru, 107 Hg, 203 Hg, 121m Te, 122m Te, 125m Te, 165 Tm, 167 Tm, 168 Tm, 197 Pt, 109 Pd, 105 Rh, I42 Pr, 143 Pr, 161 Tb, 166 Ho, 199 Au, 57 Co, 58 Co, 51 Cr, 59 Fe, 75 Se, 201 T1, 225 Ac, 76 Br, 169 Yb, and the like.
- Therapeutic agents may include a photoactive agent or dye.
- compositions such as fluorochrome, and other chromogens, or dyes, such as porphyrins sensitive to visible light
- photoradiation phototherapy
- photodynamic therapy this has been termed photoradiation, phototherapy, or photodynamic therapy.
- monoclonal antibodies have been coupled with photoactivated dyes for achieving phototherapy. See Mew et al., J. Immunol. (1983), 130: 1473; idem., Cancer Res. (1985), 45:4380; Oseroff et al, Proc. Natl. Acad. Sci. USA (1986), 83:8744; idem.,
- Corticosteroid hormones can increase the effectiveness of other chemotherapy agents, and consequently, they are frequently used in combination treatments.
- Prednisone and dexamethasone are examples of corticosteroid hormones. .
- anti-angiogenic agents such as angiostatin, baculostatin, canstatin, maspin, anti-placenta growth factor (P1GF) peptides and antibodies, anti-vascular growth factor antibodies (such as anti-VEGF and anti-PlGF), anti-Flk-1 antibodies, anti-Fit- 1 antibodies and peptides, anti-Kras antibodies, anti-cMET antibodies, anti-MIF (macrophage migration-inhibitory factor) antibodies, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin-12, IP- 10, Gro- ⁇ , thrombospondin, 2-methoxyoestradiol, proliferin-related protein,
- P1GF anti-placenta growth factor
- anti-vascular growth factor antibodies such as anti-VEGF and anti-PlGF
- anti-Flk-1 antibodies such as anti-VEGF and anti-P
- carboxiamidotriazole CM101 , Marimastat, pentosan polysulphate, angiopoietin-2, interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, Linomide, thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, angiostatin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 or minocycline may be of use.
- the therapeutic agent may comprise and oligonucleotide, such as a siRNA.
- oligonucleotide such as a siRNA.
- siRNA any siRNA or interference RNA species may be attached to a targetable construct for delivery to a targeted tissue.
- Many siRNA species against a wide variety of targets are known in the art, and any such known siRNA may be utilized in the claimed methods and compositions.
- siRNA species of potential use include those specific for IKK-gamma (U.S. Patent 7,022,828); VEGF, Flt-1 and Flk-l/KDR (U.S. Patent 7,148,342); Bcl2 and EGFR (U.S. Patent 7,541,453); CDC20 (U.S. Patent 7,550,572); transducin (beta)-like 3 (U.S.
- Patent 7,576,196 KRAS (U.S. Patent 7,576,197); carbonic anhydrase II (U.S. Patent 7,579,457); complement component 3 (U.S. Patent 7,582,746); interleukin-1 receptor- associated kinase 4 (IRAK4) (U.S. Patent 7,592,443); survivin (U.S. Patent 7,608,7070); superoxide dismutase 1 (U.S. Patent 7,632,938); MET proto-oncogene (U.S. Patent
- amyloid beta precursor protein U.S. Patent 7,635,771
- IGF-1R U.S. Patent 7,638,621
- ICAM1 U.S. Patent 7,642,349
- complement factor B U.S. Patent 7,696,344
- p53 7,781,575)
- apolipoprotein B 7,795,421
- siRNA species there are 30,852 siRNA species in the NCBI Probe database.
- the skilled artisan will realize that for any gene of interest, either a siRNA species has already been designed, or one may readily be designed using publicly available software tools. Any such siRNA species may be delivered using the subject DNL complexes.
- siRNA species known in the art are listed in Table 1. Although siRNA is delivered as a double-stranded molecule, for simplicity only the sense strand sequences are shown in Table 1. Table 1. Exemplary siRNA Sequences
- Table 1 represents a very small sampling of the total number of siRNA species known in the art, and that any such known siRNA may be utilized in the claimed methods and compositions.
- Diagnostic agents are preferably selected from the group consisting of a radionuclide, a radiological contrast agent, a paramagnetic ion, a metal, a fluorescent label, a
- Ultrasound contrast agents may comprise liposomes, such as gas filled liposomes.
- Radiopaque diagnostic agents may be selected from compounds, barium compounds, gallium compounds, and thallium compounds.
- fluorescent labels are known in the art, including but not limited to fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine.
- Chemiluminescent labels of use may include luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt or an oxalate ester.
- the invention in another aspect, relates to a method of treating a subject, comprising administering a therapeutically effective amount of a therapeutic conjugate as described herein to a subject.
- Diseases that may be treated with the therapeutic conjugates described herein include, but are not limited to B-cell malignancies (e.g., non-Hodgkin's lymphoma and chronic lymphocytic leukemia using, for example LL2 antibody; see U.S. Patent No.
- adenocarcinomas of endodermally-derived digestive system epithelia cancers such as breast cancer and non-small cell lung cancer, and other carcinomas, sarcomas, glial tumors, myeloid leukemias, etc.
- antibodies against an antigen e.g., an oncofetal antigen, produced by or associated with a malignant solid tumor or hematopoietic neoplasm, e.g., a gastrointestinal, lung, breast, prostate, ovarian, testicular, brain or lymphatic tumor, a sarcoma or a melanoma, are advantageously used.
- Such therapeutics can be given once or repeatedly, depending on the disease state and tolerability of the conjugate, and can also be used optimally in combination with other therapeutic modalities, such as surgery, external radiation, radioimmunotherapy, immunotherapy, chemotherapy, antisense therapy, interference RNA therapy, gene therapy, and the like. Each combination will be adapted to the tumor type, stage, patient condition and prior therapy, and other factors considered by the managing physician.
- the term "subject” refers to any animal (i.e., vertebrates and invertebrates) including, but not limited to mammals, including humans. It is not intended that the term be limited to a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are encompassed by the term.
- therapeutic conjugates comprising the RS7 antibody (binding to epithelial glycoprotein- 1 [EGP-1] antigen) can be used to treat carcinomas such as carcinomas of the lung, stomach, urinary bladder, breast, ovary, uterus, and prostate, as disclosed in U.S. Patent No. 7,238,785, the Examples section of which is incorporated herein by reference.
- RS7 antibody binding to epithelial glycoprotein- 1 [EGP-1] antigen
- therapeutic conjugates comprising anti-tenascin antibodies can be used to treat hematopoietic and solid tumors and conjugates comprising antibodies to tenascin can be used to treat solid tumors, preferably brain cancers like glioblastomas.
- the therapeutic conjugates can be used against pathogens, since antibodies against pathogens are known.
- antibodies and antibody fragments which specifically bind markers produced by or associated with infectious lesions, including viral, bacterial, fungal and parasitic infections, for example caused by pathogens such as bacteria, rickettsia, mycoplasma, protozoa, fungi, and viruses, and antigens and products associated with such microorganisms have been disclosed, inter alia, in Hansen et al., U.S. Pat. No. 3,927,193 and Goldenberg U.S. Pat. Nos.
- Toxoplasma gondii Trypanosoma rangeli, Trypanosoma cruzi, Trypanosoma rhodesiense, Trypanosoma brucei, Schistosoma mansoni, Schistosoma japonicum, Babesia bovis, Eimeria tenella, Onchocerca volvulus, Leishmania tropica, Trichinella spiralis, Theileria parva, Taenia hydatigena, Taenia ovis, Taenia saginata, Echinococcus granulosus, Mesocestoides corti, Mycoplasma arthritidis, M. hyorhinis, M. orale, M. arginini, Acholeplasma laidlawii, M. salivarium and M. pneumoniae, as disclosed in U.S. Patent No. 6,440,416, the Examples section of which is incorporated herein by reference.
- drug conjugates of the present invention comprising anti-gpl20 and other such anti-HIV antibodies can be used as therapeutics for HIV in AIDS patients; and drug conjugates of antibodies to Mycobacterium tuberculosis are suitable as therapeutics for drug-refractive tuberculosis.
- Fusion proteins of anti-gpl20 antibody (anti HIV antibody) and a toxin, such as Pseudomonas exotoxin have been examined for antiviral properties (Van Oigen et al., J Drug Target, 5:75-91 , 1998). Attempts at treating HIV infection in AIDS patients failed, possibly due to insufficient efficacy or unacceptable host toxicity.
- the drug conjugates of the present invention advantageously lack such toxic side effects of protein toxins, and are therefore advantageously used in treating HIV infection in AIDS patients. These drug conjugates can be given alone or in combination with other antibiotics or therapeutic agents that are effective in such patients when given alone.
- Candidate anti-HIV antibodies include the anti-envelope antibody described by Johansson et al. (AIDS. 2006 Oct 3;20(15): 191 1-5), as well as the anti-HIV antibodies described and sold by Polymun (Vienna, Austria), also described in U.S. Patent 5,831 ,034, U.S. Patent
- Typical antibodies useful in these diseases include, but are not limited to, those reactive with HLA-DR antigens, B-cell and plasma-cell antigens (e.g., CD19, CD20, CD21 , CD22, CD23, CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CD 126, CD 138, B7, MUCl , la, HM1.24, and HLA-DR), IL-6, IL-17.
- HLA-DR antigens e.g., CD19, CD20, CD21 , CD22, CD23, CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CD 126, CD 138
- autoimmune diseases are affected by autoantibodies made by aberrant B-cell populations
- depletion of these B-cells by therapeutic conjugates involving such antibodies-therapeutic agent conjugates described herein is a preferred method of autoimmune disease therapy, especially when B-cell antibodies are combined, in certain circumstances, with HLA-DR antibodies and/or T-cell antibodies (including those which target IL-2 as an antigen, such as anti-TAC antibody).
- the anti-B- cell, anti-T-cell, or anti-macrophage or other such antibodies of use in the treatment of patients with autoimmune diseases also can be conjugated to result in more effective therapeutics to control the host responses involved in said autoimmune diseases, and can be given alone or in combination with other therapeutic agents, such as TNF inhibitors or TNF antibodies, unconjugated B- or T-cell antibodies, and the like.
- a more effective incorporation into cells and pathogens can be accomplished by using multivalent, multispecific or multivalent, monospecific antibodies. Examples of such bivalent and bispecific antibodies are found in U.S. Patent Nos.
- multivalent or multispecific antibodies are particularly preferred in the targeting of cancers and infectious organisms (pathogens), which express multiple antigen targets and even multiple epitopes of the same antigen target, but which often evade antibody targeting and sufficient binding for immunotherapy because of insufficient expression or availability of a single antigen target on the cell or pathogen.
- pathogens infectious organisms
- said antibodies show a higher binding and residence time on the target, thus affording a higher saturation with the drug being targeted in this invention.
- compositions described herein are parenteral injection.
- Injection may be intravenous, intraarterial, intralymphatic, intrathecal, or intracavitary (i.e., parenterally).
- parenteral administration the compositions will be formulated in a unit dosage injectable form such as a solution, suspension or emulsion, in association with a pharmaceutically acceptable excipient.
- excipients are inherently nontoxic and nontherapeutic. Examples of such excipients are saline, Ringer's solution, dextrose solution and Hank's solution.
- Nonaqueous excipients such as fixed oils and ethyl oleate may also be used.
- a preferred excipient is 5% dextrose in saline.
- the excipient may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, including buffers and preservatives.
- Other methods of administration, including oral administration, are also contemplated.
- compositions comprising labeled molecules can be used for intravenous administration via, for example, bolus injection or continuous infusion.
- Compositions for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
- Compositions can also take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the compositions can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- compositions may be administered in solution.
- the pH of the solution should be in the range of pH 5 to 9.5, preferably pH 6.5 to 7.5.
- the formulation thereof should be in a solution having a suitable pharmaceutically acceptable buffer such as phosphate, TRIS (hydroxymethyl) aminomethane-HCl or citrate and the like. Buffer concentrations should be in the range of 1 to 100 mM.
- the formulated solution may also contain a salt, such as sodium chloride or potassium chloride in a concentration of 50 to 150 mM.
- compositions may be administered to a mammal subcutaneously, intravenously,
- the administration may be by continuous infusion or by single or multiple boluses.
- bispecific antibodies are administered, for example in a pretargeting technique
- the dosage of an administered antibody for humans will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition and previous medical history.
- Examples of dosages of bispecific antibodies that may be administered to a human subject are 1 to 200 mg, more preferably 1 to 70 mg, most preferably 1 to 20 mg, although higher or lower doses may be used. Dosages of therapeutic bispecific antibodies may be higher, such as 1 to 200, 1 to 100, 100 to 1000, 100 to 500, 200 to 750 mg or any range in between.
- the dosage of labeled molecule(s) to administer will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition and previous medical history.
- a saturating dose of the labeled molecules is administered to a patient.
- the dosage may be measured by millicuries.
- the labeled peptides, proteins and/or antibodies are of use for therapy of cancer.
- cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers are noted below and include: squamous cell cancer (e.g.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer
- cancer includes primary malignant cells or tumors (e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor) and secondary malignant cells or tumors (e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor).
- primary malignant cells or tumors e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor
- secondary malignant cells or tumors e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor.
- cancers or malignancies include, but are not limited to: Acute Childhood Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, Adult (Primary)
- Neoplasm/Multiple Myeloma Primary Central Nervous System Lymphoma, Primary Liver Cancer, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Renal Pelvis and Ureter Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoidosis Sarcomas, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Neck Cancer, Stomach Cancer, Supratentorial Primitive
- Neuroectodermal and Pineal Tumors T-Cell Lymphoma, Testicular Cancer, Thymoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Transitional Renal Pelvis and Ureter Cancer, Trophoblastic Tumors, Ureter and Renal Pelvis Cell Cancer, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma, Vulvar Cancer, Waldenstrom's Macroglobulinemia, Wilms' Tumor, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.
- the methods and compositions described and claimed herein may be used to detect or treat malignant or premalignant conditions. Such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angell, Basic Pathology, 2d Ed., W. B. Saunders Co., Philadelphia, pp. 68-79 (1976)).
- Dysplastic disorders which can be detected include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis hemimelia, dysplasia epiphysialis multiplex, dysplasia epiphysialis punctata, epi
- pseudoachondroplastic spondyloepiphysial dysplasia retinal dysplasia, septo-optic dysplasia, spondyloepiphysial dysplasia, and ventriculoradial dysplasia.
- Additional pre-neoplastic disorders which can be detected and/or treated include, but are not limited to, benign dysproliferative disorders (e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps, colon polyps, and esophageal dysplasia), leukoplakia, keratoses, Bowen's disease, Farmer's Skin, solar cheilitis, and solar keratosis.
- benign dysproliferative disorders e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps, colon polyps, and esophageal dysplasia
- leukoplakia keratoses
- Bowen's disease keratoses
- Farmer's Skin Farmer's Skin
- solar cheilitis solar cheilitis
- Additional hyperproliferative diseases, disorders, and/or conditions include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, lipos
- lymphangioendotheliosarcoma synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma,
- exemplary conditions listed above that may be treated are not limiting.
- the skilled artisan will be aware that antibodies, antibody fragments or targeting peptides are known for a wide variety of conditions, such as autoimmune disease, graft- versus-host- disease, organ transplant rejection, cardiovascular disease, neurodegenerative disease, metabolic disease, cancer, infectious disease and hyperproliferative disease.
- Exemplary autoimmune diseases include acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, juvenile diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thro
- granulomatosis membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, psoriasis and fibrosing alveolitis.
- kits containing components suitable for treating diseased tissue in a patient may contain at least one conjugated antibody or other targeting moiety as described herein. If the composition containing components for administration is not formulated for delivery via the alimentary canal, such as by oral delivery, a device capable of delivering the kit components through some other route may be included.
- a device capable of delivering the kit components through some other route may be included.
- the kit components may be packaged together or separated into two or more containers.
- the containers may be vials that contain sterile, lyophilized formulations of a composition that are suitable for reconstitution.
- a kit may also contain one or more buffers suitable for reconstitution and/or dilution of other reagents.
- Other containers that may be used include, but are not limited to, a pouch, tray, box, tube, or the like. Kit components may be packaged and maintained sterilely within the containers.
- Another component that can be included is instructions to a person using a kit for its use.
- the DNL technique can be used to make dimers, trimers, tetramers, hexamers, etc. comprising virtually any antibody, antibody fragment, or other effector moiety.
- the antibodies and antibody fragments may be produced as fusion proteins comprising either a dimerization and docking domain (DDD) or anchoring domain (AD) sequence.
- DDD dimerization and docking domain
- AD anchoring domain
- other methods of conjugation exist, such as chemical cross-linking, click chemistry reaction, etc.
- the technique is not limiting and any protein or peptide of use may be produced as an AD or DDD fusion protein for incorporation into a DNL construct.
- the AD and DDD conjugates may comprise any molecule that may be cross-linked to an AD or DDD sequence using any cross-linking technique known in the art.
- a dendrimer or other polymeric moiety such as polyethylene glycol (PEG) may be incorporated into a DNL construct, as described in further detail below.
- AD or DDD sequences may be utilized. Exemplary DDD and AD sequences are provided below.
- DDD1 SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (SEQ ID NO:33)
- AD2 CGQIEYLAKQIVDNAIQQAGC (SEQ ID NO:36) [0147]
- DDDl and DDD2 comprise the DDD sequence of the human RIIcc form of protein kinase A.
- the DDD and AD moieties may be based on the DDD sequence of the human RIa form of protein kinase A and a corresponding AKAP sequence, as exemplified in DDD3, DDD3C and AD3 below.
- the plasmid vector pdHL2 has been used to produce a number of antibodies and antibody-based constructs. See Gillies et al., J Immunol Methods (1989), 125: 191-202; Losman et al, Cancer (Phila) (1997), 80:2660-6.
- the di-cistronic mammalian expression vector directs the synthesis of the heavy and light chains of IgG.
- the vector sequences are mostly identical for many different IgG-pdHL2 constructs, with the only differences existing in the variable domain (VH and VL) sequences. Using molecular biology tools known to those skilled in the art, these IgG expression vectors can be converted into Fab-DDD or Fab- AD expression vectors.
- Fab-DDD expression vectors To generate Fab-DDD expression vectors, the coding sequences for the hinge, CH2 and CH3 domains of the heavy chain are replaced with a sequence encoding the first 4 residues of the hinge, a 14 residue Gly-Ser linker and the first 44 residues of human Rlla (referred to as DDDl).
- AD1 AKAP-ZS
- Two shuttle vectors were designed to facilitate the conversion of IgG-pdHL2 vectors to either Fab-DDDl or Fab-ADl expression vectors, as described below.
- a duplex oligonucleotide was synthesized to code for the amino acid sequence of DDD1 preceded by 1 1 residues of the linker peptide, with the first two codons comprising a BamHI restriction site. A stop codon and an Eagl restriction site are appended to the 3'end.
- the encoded polypeptide sequence is shown below.
- oligonucleotides designated RIIA1-44 top and RIIA1-44 bottom, which overlap by 30 base pairs on their 3' ends, were synthesized and combined to comprise the central 154 base pairs of the 174 bp DDD1 sequence.
- the oligonucleotides were annealed and subjected to a primer extension reaction with Taq polymerase. Following primer extension, the duplex was amplified by PCR. The amplimer was cloned into PGEMT® and screened for inserts in the T7 (5') orientation.
- AKAP-IS Top Two complimentary overlapping oligonucleotides encoding the above peptide sequence, designated AKAP-IS Top and AKAP-IS Bottom, were synthesized and annealed. The duplex was amplified by PCR. The amplimer was cloned into the PGEMT® vector and screened for inserts in the T7 (5') orientation. Ligating DDD1 with CHI
- a 1 10 bp fragment containing the AD1 sequence was excised from PGEMT® with BamHI and Notl and then ligated into the same sites in CHI -PGEMT® to generate the shuttle vector CHI -AD 1 -PGEMT®.
- CH1-DDD1 or CH1-AD1 can be incorporated into any IgG construct in the pdHL2 vector.
- the entire heavy chain constant domain is replaced with one of the above constructs by removing the SaclI/EagI restriction fragment (CH1-CH3) from pdHL2 and replacing it with the SaclI/EagI fragment of CH1-DDD1 or CH1-AD1, which is excised from the respective pGemT shuttle vector.
- h679-Fd-ADl-pdHL2 is an expression vector for production of h679 Fab with AD1 coupled to the carboxyl terminal end of the CHI domain of the Fd via a flexible Gly/Ser peptide spacer composed of 14 amino acid residues.
- a pdHL2-based vector containing the variable domains of h679 was converted to h679-Fd-ADl-pdHL2 by replacement of the SaclI/EagI fragment with the CH1-AD1 fragment, which was excised from the CH1-AD1- SV3 shuttle vector with SacII and Eagl.
- C-DDDl-Fd-hMN-14-pdHL2 is an expression vector for production of a stable dimer that comprises two copies of a fusion protein C-DDDl-Fab-hMN-14, in which DDD1 is linked to hMN-14 Fab at the carboxyl terminus of CHI via a flexible peptide spacer.
- the plasmid vector hMN-14(I)-pdHL2 which has been used to produce hMN-14 IgG, was converted to C-DDDl-Fd-hMN-14-pdHL2 by digestion with SacII and Eagl restriction endonucleases to remove the CH1-CH3 domains and insertion of the CH1-DDD1 fragment, which was excised from the CH1-DDD1-SV3 shuttle vector with SacII and Eagl.
- AD- and DDD-fusion proteins comprising a Fab fragment of any of such antibodies may be combined, in an approximate ratio of two DDD-fusion proteins per one AD-fusion protein, to generate a trimeric DNL construct comprising two Fab fragments of a first antibody and one Fab fragment of a second antibody.
- N-DDDl-Fd-hMN-14-pdHL2 is an expression vector for production of a stable dimer that comprises two copies of a fusion protein N-DDDl-Fab-hMN-14, in which DDD1 is linked to hMN-14 Fab at the amino terminus of VH via a flexible peptide spacer.
- the expression vector was engineered as follows. The DDD1 domain was amplified by PCR.
- the N-DDD1 -hMN-14 Fd sequence was excised with Xhol and Eagl restriction enzymes and the 1.28 kb insert fragment was ligated with a vector fragment that was prepared by digestion of C-hMN-14-pdHL2 with those same enzymes.
- the final expression vector was N-DDDl -Fd-hMN-14-pDHL2.
- the N-linked Fab fragment exhibited similar DNL complex formation and antigen binding characteristics as the C-linked Fab fragment (not shown).
- C-DDD2-Fd-hMN-14-pdHL2 is an expression vector for production of C-DDD2-Fab- hMN-14, which possesses a dimerization and docking domain sequence of DDD2 appended to the carboxyl terminus of the Fd of hMN-14 via a 14 amino acid residue Gly/Ser peptide linker.
- the fusion protein secreted is composed of two identical copies of hMN-14 Fab held together by non-covalent interaction of the DDD2 domains.
- the expression vector was engineered as follows. Two overlapping, complimentary oligonucleotides, which comprise the coding sequence for part of the linker peptide and residues 1-13 of DDD2, were made synthetically. The oligonucleotides were annealed and phosphorylated with T4 PNK, resulting in overhangs on the 5' and 3' ends that are compatible for ligation with DNA digested with the restriction endonucleases BamHI and Pstl, respectively.
- the duplex DNA was ligated with the shuttle vector CH1-DDD1 -PGEMT®, which was prepared by digestion with BamHI and Pstl, to generate the shuttle vector CH1 -DDD2- PGEMT®.
- a 507 bp fragment was excised from CH 1 -DDD2-PGEMT® with Sacll and EagI and ligated with the IgG expression vector hMN-14(I)-pdHL2, which was prepared by digestion with Sacll and EagI.
- the final expression construct was designated C-DDD2-Fd- hMN-14-pdHL2. Similar techniques have been utilized to generated DDD2-fusion proteins of the Fab fragments of a number of different humanized antibodies. h679-Fd-AD2-pdHL2
- h679-Fab-AD2 was designed to pair as B to C-DDD2-Fab-hMN- 14 as A.
- h679-Fd- AD2-pdHL2 is an expression vector for the production of h679-Fab-AD2, which possesses an anchoring domain sequence of AD2 appended to the carboxyl terminal end of the CHI domain via a 14 amino acid residue Gly/Ser peptide linker.
- AD2 has one cysteine residue preceding and another one following the anchor domain sequence of AD1.
- the expression vector was engineered as follows. Two overlapping, complimentary oligonucleotides (AD2 Top and AD2 Bottom), which comprise the coding sequence for AD2 and part of the linker sequence, were made synthetically. The oligonucleotides were annealed and phosphorylated with T4 PNK, resulting in overhangs on the 5' and 3' ends that are compatible for ligation with DNA digested with the restriction endonucleases BamHI and Spel, respectively.
- TF1 A large scale preparation of a DNL construct, referred to as TF1 , was carried out as follows. N-DDD2-Fab-hMN- 14 (Protein L-purified) and h679-Fab-AD2 (IMP-291 -purified) were first mixed in roughly stoichiometric concentrations in ImM EDTA, PBS, pH 7.4. Before the addition of TCEP, SE-HPLC did not show any evidence of a 2 b formation (not shown). Instead there were peaks representing a 4 (7.97 min; 200 kDa), a 2 (8.91 min; 100 kDa) and B (10.01 min; 50 kDa).
- TF2 was purified to near homogeneity by IMP 291 affinity chromatography (not shown).
- IMP 291 is a synthetic peptide containing the HSG hapten to which the 679 Fab binds (Rossi et al., 2005, Clin Cancer Res 1 l :7122s-29s).
- SE-HPLC analysis of the IMP 291 unbound fraction demonstrated the removal of a4, a 2 and free kappa chains from the product (not shown).
- TF10 DNL construct comprising two copies of a C-DDD2-Fab-hPAM4 and one copy of C-AD2-Fab-679.
- the cancer- targeting antibody component in TF10 was derived from hPAM4, a humanized anti- pancreatic cancer mucin MAb that has been studied in detail as a radiolabeled MAb ⁇ e.g., Gold et al, Clin. Cancer Res. 13 : 7380-7387, 2007).
- the hapten-binding component was derived from h679, a humanized anti-histaminyl-succinyl-glycine (HSG) MAb.
- the TF10 bispecific ([hPAM4] 2 x h679) antibody was produced using the method disclosed for production of the (anti CEA) 2 x anti HSG bsAb TF2, as described above.
- the TF10 construct bears two humanized PAM4 Fabs and one humanized 679 Fab.
- the two fusion proteins (hPAM4-DDD and h679-AD2) were expressed independently in stably transfected myeloma cells.
- the tissue culture supernatant fluids were combined, resulting in a two-fold molar excess of hPAM4-DDD.
- the reaction mixture was incubated at room temperature for 24 hours under mild reducing conditions using 1 mM reduced glutathione.
- TF10 was isolated by affinity chromatography using IMP 291 -affigel resin, which binds with high specificity to the h679 Fab.
- DNL techniques may be used to produce complexes comprising any combination of antibodies, immunoconjugates, or other effector moieties that may be attached to an AD or DDD moiety.
- the IgG and Fab fusion proteins shown in Table 2 were constructed and incorporated into DNL constructs.
- the fusion proteins retained the antigen-binding characteristics of the parent antibodies and the DNL constructs exhibited the antigen-binding activities of the incorporated antibodies or antibody fragments.
- the AD and DDD sequences incorporated into the DNL construct comprise the amino acid sequences of AD1 , AD2, AD3, DDDl, DDD2, DDD3 or DDD3C as discussed above.
- sequence variants of AD and/or DDD moieties may be utilized in construction of the DNL complexes.
- the Rlla DDD sequence is the basis of DDDl and DDD2 disclosed above.
- the four human PKA DDD sequences are shown below.
- the DDD sequence represents residues 1-44 of Rlla, 1-44 of RIIp, 12-61 of RIa and 13-66 of Rip. (Note that the sequence of DDDl is modified slightly from the human PKA Rlla DDD moiety.)
- AKAP-IS RII selective AD sequence
- the AKAP-IS sequence was designed as a peptide antagonist of AKAP binding to PKA. Residues in the AKAP-IS sequence where substitutions tended to decrease binding to DDD are underlined in SEQ ID NO:35.
- sequence variants of the AD sequence one would desirably avoid changing any of the underlined residues, while conservative amino acid substitutions might be made for residues that are less critical for DDD binding.
- Figure 2 of Gold et al. disclosed additional DDD-binding sequences from a variety of AKAP proteins, shown below.
- AKAP7 ⁇ 5-wt-pep PEDAELVRLSKRLVENAVLKAVQQY (SEQ ID NO:66) AKAP7 ⁇ $-L304T-pep PEDAELVRTSKRLVENAVLKAVQQY (SEQ ID NO:67) AKAP7J-L308D-pep PEDAELVRLSKRDVENAVLKAVQQY (SEQ ID NO:68) AKAP7(5-P-pep PEDAELVRLSKRLPENAVLKAVQQY (SEQ ID NO:69) AKAP7J-PP-pep PEDAELVRLSKRLPENAPLKAVQQY (SEQ ID NO:70) AKAP7 ⁇ 5-L314E-pep PED AEL VRLSKRL VEN A VEKA V QQ Y (SEQ ID NO:71) AKAP 1 -pep EEGLDRNEEIKRAAFQIISQVISEA (SEQ ID NO:72)
- AKAP12-pep NGILELETKSSKLVQNIIQTAVDQF (SEQ ID NO:78)
- E1-G5/2 was prepared by combining two self-assembling modules, AD2-G5/2 and hRS7-Fab-DDD2, under mild redox conditions, followed by purification on a Protein L column.
- AD2-G5/2 we derivatized the AD2 peptide with a maleimide group to react with the single thiol generated from reducing a G5 PAMAM with a cystamine core and used reversed-phase HPLC to isolate AD2-G5/2.
- hRS7-Fab-DDD2 as a fusion protein in myeloma cells, as described in the Examples above.
- E1 -G5/2 The molecular size, purity and composition of E1 -G5/2 were analyzed by size- exclusion HPLC, SDS-PAGE, and Western blotting. The biological functions of E1-G5/2 were assessed by binding to an anti-idiotype antibody against hRS7, a gel retardation assay, and a DNase protection assay.
- E1-G5/2 was shown by size-exclusion HPLC to consist of a major peak (>90%) flanked by several minor peaks.
- the three constituents of E1-G5/2 (Fd-DDD2, the light chain, and AD2-G5/2) were detected by reducing SDS-PAGE and confirmed by Western blotting.
- Anti-idiotype binding analysis revealed E1-G5/2 contained a population of antibody-dendrimer conjugates of different size, all of which were capable of recognizing the anti-idiotype antibody, thus suggesting structural variability in the size of the purchased G5 dendrimer.
- the DNL technique can be used to build dendrimer-based nanoparticles that are targetable with antibodies.
- Such agents have improved properties as carriers of drugs, plasmids or siRNAs for applications in vitro and in vivo.
- the peptide IMP 498 up to and including the PEG moiety was synthesized on a Protein Technologies PS3 peptide synthesizer by the Fmoc method on Sieber Amide resin (0.1 mmol scale).
- the maleimide was added manually by mixing the ⁇ -maleimidopropionic acid NHS ester with diisopropylethylamine and DMF with the resin for 4 hr.
- the peptide was cleaved from the resin with 15 mL TFA, 0.5 mL H 2 0, 0.5 mL triisopropylsilane, and 0.5 mL thioanisole for 3 hr at room temperature.
- the peptide was purified by reverse phase HPLC using H2O/CH3CN TFA buffers to obtain about 90 mg of purified product after
- the bispecific antibody (bsMAb) is administered first to the subject and allowed to localize to a targeted cell or tissue.
- a clearing agent may be administered to expedite clearance of the bsMAb from circulation.
- a targetable construct is administered that binds to the bsMAb localized in the target tissue.
- the targetable construct is conjugated to one or more therapeutic and/or diagnostic agents. Because the targetable construct clears very rapidly from circulation and is typically excreted intact, primarily in the urine, the cytotoxic therapeutic agent spends little time in circulation and is not taken up by non-targeted tissues, thus reducing systemic toxicity.
- the object of the present Example was to develop novel reagents for use in therapeutic pretargeting. These were tested in an animal model for human colorectal cancer, using an anti-carcinoembryonic antigen (CEACAM5) bispecific antibody. An exemplary cytotoxic drug used in the pretargeting study was SN-38.
- a core peptide targetable construct described in detail below (IMP 457), was developed.
- the targetable construct was modified to attach SN-38 and can attach up to 4 SN- 38 moieties per core peptide.
- a dendron polymer was also prepared that can bind 8 to 16 SN- 38 moieties per polymer molecule.
- the targetable construct has the ability to bind both therapeutic radionuclides and chemotherapeutic agents for combination therapy of diseased tissues, such as cancer.
- An exemplary bispecific antibody used was the TF2 DNL construct, described in the Examples above. TF2 contains two CEACAM5-binding hMN-14 Fab moieties and one HSG-binding h679 Fab moiety.
- the targetable construct contained two HSG haptens per peptide to allow cross-linking of two TF2 bsMAbs at the tumor surface.
- Cross-linking of the two bispecific antibodies enhances the retention of pretargeted peptide on the tumor surface (Barbet et al., 1999, Cancer Biother Radiopharm 14: 153-66).
- the peptide-drug conjugates are designed to allow for the slow release of the drug, for example with a drug linkage that is stable for up to 1 day, but then released in a time-dependent manner.
- direct drug-antibody conjugates that are retained in the body for sustained periods, allowing catabolism in the liver and other organs, in pretargeting most of the injected product is excreted intact to minimize systemic side effects. But the drug-peptide conjugate localized in the tumor is slowly released within the tumor.
- IMP 402 was synthesized on Sieber amide resin as follows. Aloc-D-Lys(Fmoc)-OH was attached to the resin. The lysine side chain Fmoc was removed and the N-Trityl- histaminyl-succinyl-glycyl group (Trityl-HSG-OH) was attached. The Aloe group was removed from the lysine and the Fmoc-D-Tyr(But)-OH was added to the peptide. Another Aloc-D-Lys(Fmoc)-OH was added to the peptide and the Trityl-HSG-OH group was added to that lysine side chain.
- the Aloe group was removed from the lysine and Fmoc-D-Ala-OH, Fmoc-D-Cys(Trt)-OH and Tri-t-butyl-DOTA-OH were added to the peptide using standard peptide coupling methods.
- the peptide was cleaved from the resin and purified by HPLC.
- dendron carrier molecule is asymmetrical, with surface groups and a focal functional group for differential substitutions. Attachment of the bis-HSG peptide at the defined focal site results in site-specific placement.
- a PAMAM dendron is exemplified in FIG. 3, although other dendrons may be used with up to sixteen surface groups. Briefly, this involves multiple derivatizations with acetylene groups for introducing multiple molecules of SN-38 via azide-yne click cycloaddition, as discussed above.
- the focal functional group is transformed by 'BOC deprotection and derivatization to a maleimide, which is conjugated to a cysteine-containing-bis-HSG peptide for pretargeting.
- the same peptide also contains a DOTA molecule that will enable labeling with In- 1 1 1 radiolabel for determining in vivo targeting.
- Dendron with either amino group or some other group on the surface is purchased if found to be cost effective. Alternatively, the dendron specified is made in-house by an iterative sequence of methacrylate reaction and ethylene diamine-based esterolysis, starting with mono-protected 1 ,6-diaminohexane.
- the BOC-protected amino group serves as the focal functional group that will ultimately carry the bis-HSG peptide site-selectively.
- an azido-SN-38 moiety may be prepared to react with a cyclooctyne or alkyne moiety on the targetable construct.
- An exemplary preparation is shown in FIG. 4.
- SN-38 silyl ether (intermediate 1) has been prepared in a number of small scale reactions as well as in one large scale reaction, using 3.43 g SN-38 with reproducibly >74% yield.
- the carbonate (intermediate 3) was prepared five times, using cross-linker as a limiting reagent in quantities in the range of 0.24-2.0 g, to obtain the purified carbonate in 0.33-2.63 g
- the azido-SN- 38 which is intermediate 4 in FIG. 4, is used for click cycloaddition to acetylene groups on the dendrimer.
- the final reaction in the synthetic sequence is the removal of 'MMT' group using a mild acid, such as dichloroacetic acid, which proceeds in a high yield.
- a mild acid such as dichloroacetic acid
- the click cycloaddition will also be examined in aqueous reaction condition involving copper sulfate and ascorbate, using DMSO as cosolvent.
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CA2782398A CA2782398C (en) | 2009-12-09 | 2010-12-09 | Delivery system for cytotoxic drugs by bispecific antibody pretargeting |
CN2010800526498A CN102665757A (en) | 2009-12-09 | 2010-12-09 | Delivery system for cytotoxic drugs by bispecific antibody pretargeting |
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US12/644,146 US7981398B2 (en) | 2005-04-06 | 2009-12-22 | PEGylation by the dock and lock (DNL) technique |
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US12/731,781 US8003111B2 (en) | 2005-04-06 | 2010-03-25 | Dimeric alpha interferon pegylated site-specifically shows enhanced and prolonged efficacy in vivo |
US12/752,649 US8034352B2 (en) | 2005-04-06 | 2010-04-01 | Tetrameric cytokines with improved biological activity |
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US12/754,740 US8562988B2 (en) | 2005-10-19 | 2010-04-06 | Strategies for improved cancer vaccines |
US12/869,823 US20110020273A1 (en) | 2005-04-06 | 2010-08-27 | Bispecific Immunocytokine Dock-and-Lock (DNL) Complexes and Therapeutic Use Thereof |
US12/869,823 | 2010-08-27 | ||
US12/871,345 US8551480B2 (en) | 2004-02-13 | 2010-08-30 | Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity |
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US12/915,515 US20110064754A1 (en) | 2005-03-03 | 2010-10-29 | Immunoconjugates Comprising Poxvirus-Derived Peptides and Antibodies Against Antigen-Presenting Cells for Subunit-Based Poxvirus Vaccines |
US12/949,536 US8211440B2 (en) | 2005-10-19 | 2010-11-18 | Multivalent immunoglobulin-based bioactive assemblies |
US12/949,536 | 2010-11-18 |
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CN104771764A (en) * | 2015-04-14 | 2015-07-15 | 中国药科大学 | Macrophage targeting carrier system and preparation method thereof |
US20160287732A1 (en) * | 2015-01-09 | 2016-10-06 | Immunomedics, Inc. | Tumor therapy by bispecific antibody pretargeting |
WO2017211278A1 (en) * | 2016-06-06 | 2017-12-14 | Asclepiumm Taiwan Co., Ltd | Antibody fusion proteins for drug delivery |
US10668167B2 (en) | 2016-06-02 | 2020-06-02 | Abbvie Inc. | Glucocorticoid receptor agonist and immunoconjugates thereof |
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CN103087171B (en) * | 2012-12-24 | 2015-01-14 | 中国人民解放军第四军医大学 | Bispecific antibody of resisting PSMA/FITC (prostate specific membrane antigen/fluorescein isothiocyanate) for early diagnosis and treatment of prostatic cancer and preparation method of bispecific antibody |
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WO2019234241A1 (en) * | 2018-06-07 | 2019-12-12 | Oncoone Research & Development Gmbh | ANTI-oxMIF/ANTI-CD3 ANTIBODY FOR CANCER TREATMENT |
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CA2782398C (en) | 2017-09-26 |
CA2782398A1 (en) | 2011-06-16 |
EP2509630A4 (en) | 2013-07-17 |
CN102665757A (en) | 2012-09-12 |
EP2509630A1 (en) | 2012-10-17 |
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