WO2023075790A1 - Kits and containers for treating vimentin expressing tumors - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- the blood brain barrier poses a significant barrier for the delivery of therapeutics to the brain.
- the BBB is a protective endothelial tissue surrounding the CNS and poses a major obstacle to the systemic delivery of therapeutic and diagnostic agents for the treatment of neurological diseases.
- treatment of brain cancer or metastases of other solid tumors to the brain is a highly unmet need.
- the lack of good treatments is due to the invasive and infiltrating character of tumors in the brain, and the inability of most effective biologic agents to cross the BBB. If the BBB were leaky or can readily be overcome, then new and useful drugs could be delivered to brain tissues. Previous products designed to overcome or bypass the BBB have been difficult to control thereby limiting their usefulness.
- the present disclosure satisfies these and other needs by providing antibodies or antibody fragments that are able to cross the BBB.
- containers comprising a composition comprising an antibody comprising a heavy chain comprising SEQ ID NO: 1 and a light chain comprising SEQ ID NO:2.
- the containers can be bottles or vials, for example, glass or polyethylene terephthalate G (PETG) bottles or vials.
- kits comprising the containers and methods of treating cancer using the antibodies from the containers.
- Figure l is graph showing clinical drug substance antibody lots stored in PETG serum vials is more potent than clinical drug substance antibody lots stored in polypropylene (PP) vials.
- Figure 2 is a graph showing the drug substance antibody lot used as a reference standard in toxicology assays has different potency in PP vials versus PETG vials.
- the antibody stored in PETG vials is more potent than antibody stored in PP vials.
- Figure 3 is a histogram plot from flow cytometry showing pritumumab binds to the cell surface of U251 glioma cells. The left peak is unstained cells and the peak shifted to the right is pritumumab staining.
- Figure 4 is a graph showing recombinant human vimentin can compete pritumumab binding to glioma cells.
- the graph is a histogram plot showing unstained cells outlined in the far left peak, pritumumab alone (160nM) outlined in the far right peak, pritumumab (160nM) ⁇ vimentin (45nM) is outlined in the far right peak overlapping the peak of pritumumab alone, and pritumumab (160nM) + vimentin (450nM) is outlined in the second peak from the left.
- Figures 5A and 5B are photos of images from whole slide scans showing representative fields in central nervous system (CNS) neoplasms.
- Figures 6A and 6B are photos of images from whole slide scans showing representative fields in normal cerebellum.
- “Vertebrate,” “mammal,” “subject,” “mammalian subject,” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, cows, horses, goats, and other animals. Animals include all vertebrates, e.g., mammals and non-mammals, such as mice, sheep, dogs, cows, avian species, ducks, geese, pigs, chickens, amphibians, and reptiles.
- Treating” or “treatment” refers generally to either (i) the prevention of disease, e.g., prophylaxis, or (ii) the reduction or elimination of symptoms of a disease of interest, e.g., therapy.
- treatment can be prophylactic (to prevent or delay the onset of the disease, or to prevent the manifestation of clinical or subclinical symptoms thereof) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease.
- Preventing or “prevention” refers to prophylactic administration with compositions of the invention.
- “Therapeutically-effective amount” or “an effective amount” refers to an amount of an antibody composition that is sufficient to prevent a disease or to alleviate (e.g., mitigate, decrease, reduce) at least one of the symptoms associated with a disease. It is not necessary that the administration of the composition totally eliminate the symptoms of the disease, as long as the benefits of administration of the composition outweigh the detriments.
- the terms “treat” and “treating” in reference to a disease, as used herein, are not intended to mean that the subject is necessarily cured of the disease or that all clinical signs thereof are eliminated, only that some alleviation or improvement in the condition of the subject is effected by administration of the composition.
- cancer refers to all types of cancer, neoplasm, or malignant tumors found in mammals, including leukemia, carcinomas and sarcomas.
- exemplary cancers include cancer of the brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma.
- Additional examples include, Hodgkin's Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, glioblastoma, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine and exocrine pancreas, and prostate cancer.
- antibody refers to any immunoglobulin or intact molecule as well as to fragments thereof that bind to a specific epitope. Such antibodies include, but are not limited to polyclonal, monoclonal, chimeric, humanized, single chain, Fab, Fab’, F(ab)’ fragments and/or F(v) portions of the whole antibody and variants thereof. All isotypes are encompassed by this term, including IgA, IgD, IgE, IgG, and IgM.
- An intact “antibody” comprises at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
- Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, CHi, CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
- the light chain constant region is comprised of one domain, CL.
- the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
- the term antibody includes antigenbinding portions of an intact antibody that retain capacity to bind.
- binding examples include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab’)z fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature, 341:544-546 (1989)), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
- a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CHI domains
- a F(ab’)z fragment a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region
- a Fd fragment
- CDR refers to one of the six hypervariable regions within the variable domains of an antibody that mainly contribute to antigen binding.
- One of the most commonly used definitions for the six CDRs was provided by Kabat E. A. et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242).
- single chain antibodies or “single chain Fv (scFv)” refers to an antibody fusion molecule of the two domains of the Fv fragment, VL and VH.
- the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., Science, 242:423-426 (1988); and Huston et al., Proc Natl Acad Sci USA, 85:5879-5883 (1988)).
- scFv single chain Fv
- Such single chain antibodies are included by reference to the term “antibody” fragments and can be prepared by recombinant techniques or enzymatic or chemical cleavage of intact antibodies.
- the containers comprise a pharmaceutical composition comprising the antibody.
- the containers comprise a therapeutically effective amount of the antibody.
- the container is a bottle or vial.
- the containers can be made out of glass or polyethylene terephthalate G (PETG).
- PETG polyethylene terephthalate G
- the container is a glass vial or a PETG vial.
- the container is a vial and the vial comprises from 5 mg/ml to 15 mg/ml of the antibody.
- DIQMTQ SP S SL S AS VGDRVTITCRASQDISNYLAWFQQKPGK APKSLIYAAS SLHSKVPTQ FSGSGSGTDFTLTISSLQPEDFATYYCLQYSTYPITFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC
- the antibody has an isoelectric point of 8.0-9.0.
- the antibody has an isoelectric point of about 8.7.
- the antibody has a median binding effective concentration (EC50) of between 8 to 9 ug/ml.
- the EC50 of the antibody in the glass vial is between 8 to 9 ug/ml.
- the EC50 of the antibody in the glass vial is between 9 to 12 ug/ml.
- the EC50 values of the antibody are those as determined using the conditions described in the examples. In other words, the antibody can have an EC50 value between 9 to 12 ug/ml under the conditions described in the examples below.
- the herein provided antibody comprising a heavy chain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:2, sometimes referred to as pritumumab, crosses the blood brain barrier. See, for U.S. Patent No. 11,028,155, which is incorporated by reference herein in its entirety.
- the antibody binds vimentin.
- the vimentin is located on the surface of a cancer cell or has been secreted by the cancer cell and is located externally to the cancer cell.
- the cancer is brain cancer.
- the containers containing the antibodies can be stored over a long period of time.
- the period of time is 3, 6, 9, 12, 15, 18, 21, or 24 months or longer.
- the antibodies can be stored at a temperature of -60°C or below.
- the antibody retains its activity over 3 freeze/thaw cycles.
- the antibody can be conjugated to an agent.
- the agent is a therapeutic agent or a diagnostic agent.
- the therapeutic agent is a chemotherapeutic agent.
- the diagnostic agent is a fluorescent agent, radioactive agent or chemiluminescent agent.
- kits for delivering an antibody across a blood brain barrier comprising administering the herein provided antibody from the containers, e.g., bottles or vials, described herein to a subject thereby delivering the antibody across the blood brain barrier.
- the containers are glass or PETG containers.
- the provided antibodies disclosed herein can be conjugated to an agent, e.g., a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin.
- agent e.g., a therapeutic moiety
- cytotoxin e.g., a cytotoxin
- drug e.g., an immunosuppressant
- radiotoxin e.g., an immunosuppressant
- the antibody conjugates of the invention can be used to modify a given biological response, and the drug moiety is not to be construed as limited to classical chemical therapeutic agents.
- the drug moiety may be a protein or polypeptide possessing a desired biological activity.
- proteins may include, for example, an enzymatically active toxin, or active fragment thereof, such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor or interferon-y; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
- IL-1 interleukin-1
- IL-2 interleukin-2
- IL-6 interleukin-6
- composition comprising an antibody comprising a heavy chain and a light chain, the heavy chain comprising a sequence of SEQ ID NO: 1 and the light chain comprising a sequence of SEQ ID NO:2 and one or more agents, e.g., imaging or therapeutic agents.
- the agents are conjugated to the antibody.
- the therapeutic agent is a chemotherapeutic agent.
- the conjugate comprises a recombinant antigen binding protein as described herein conjugated to one or more agents.
- the composition is formulated for delivery to the brain.
- the composition is capable of crossing the blood brain barrier.
- the heavy chain of the antibody comprises SEQ ID NO: 1 and the light chain comprises SEQ ID NO:2.
- the antibody is pritumumab.
- Suitable therapeutic agents for use in the provided compositions and methods, e g., for conjugation to the provided antibodies include, but are not limited to, therapeutic agent is selected from the group consisting of analgesics, anesthetics, analeptics, corticosteroids, anticholinergic agents, anticholinesterases, anticonvulsants, antineoplastic agents, allosteric inhibitors, anabolic steroids, antirheumatic agents, psychotherapeutic agents, neural blocking agents, antiinflammatory agents, antihelmintics, antibiotics, anticoagulants, antifungals, antihistamines, antimuscarinic agents, antimycobacterial agents, antiprotozoal agents, antiviral agents, dopaminergics, hematological agents, immunological agents, muscarinics, protease inhibitors, vitamins, growth factors, and hormones.
- therapeutic agent is selected from the group consisting of analgesics, anesthetics, analeptics, corticosteroids, anticholinergic agents, anticho
- the antibodies can be linked or conjugated to an imaging agent.
- Imaging agents and their use are known.
- the imaging agent is a “detectable moiety,” which is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means.
- useful labels include 32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.
- the detectable moiety can be selected from the group consisting of gamma-emitters, betaemitters, and alpha-emitters, gamma-emitters, positron-emitters, X-ray-emitters and fluorescence- emitters.
- Suitable fluorescent compounds include fluorescein sodium, fluorescein isothiocyanate, phycoerythrin, and Texas Red sulfonyl chloride, Allophycocyanin (APC), Cy5-PE, CY7-APC, and Cascade yellow.
- the detectable moiety can be visualized using histochemical techniques, ELISA- like assays, confocal microscopy, fluorescent detection, cell sorting methods, nuclear magnetic resonance, radioimmunoscintigraphy, X-radiography, positron emission tomography, computerized axial tomography, magnetic resonance imaging, and ultrasonography.
- a “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means.
- useful labels include 32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.
- the presently disclosed subject matter provides containers comprising pharmaceutical compositions comprising the antibodies provided in the present disclosure.
- the antibodies according to the present disclosure can be administered to subjects with one or more additional agents, for example, antiviral or anticancer drugs or analgesics.
- compositions can also contain a pharmaceutically acceptable carrier or adjuvant for administration of the antibody or antigen binding protein.
- the carrier is pharmaceutically acceptable for use in humans.
- the carrier or adjuvant should not itself induce the production of antibodies harmful to the individual receiving the composition and should not be toxic.
- Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, ammo acid copolymers and inactive virus particles.
- salts can be used, for example mineral acid salts, such as hydrochlorides, hydrobromides, phosphates and sulphates, or salts of organic acids, such as acetates, propionates, malonate and benzoates.
- mineral acid salts such as hydrochlorides, hydrobromides, phosphates and sulphates
- organic acids such as acetates, propionates, malonate and benzoates.
- compositions in therapeutic compositions can additionally contain liquids such as water, saline, glycerol and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents or pH buffering substances, can be present in such compositions. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions, for ingestion by the patient.
- the compositions of the presently disclosed subject matter can further comprise a carrier to facilitate composition preparation and administration. Any suitable delivery vehicle or carrier can be used, including but not limited to a microcapsule, for example a microsphere or a nanosphere (Manome et al.
- Antibody sequences can be coupled to active agents or carriers using methods known in the art, including but not limited to carbodiimide conjugation, esterification, sodium periodate oxidation followed by reductive alkylation, and glutaraldehyde crosslinking (Goldman et al. (1997) Cancer Res. 57: 1447-1451; Cheng (1996) Hum. Gene Ther. 7:275-282; Neri et al. (1997) Nat. Biotechnol. 15: 1271-1275; Nabel (1997) Vectors for Gene Therapy. In Current Protocols in Human Genetics, John Wiley & Sons, New York; Park et al. (1997) Adv. Pharmacol. 40:399-435; Pasqualini et al. (1997) Nat. Biotechnol. 15:542-546; Bauminger & Wilchek (1980) Meth. Enzymol. 70:151-159; U.S. Pat. No. 6,071,890; and European Patent No. 0 439 095).
- a therapeutic composition of the present invention comprises in some embodiments a pharmaceutical composition that includes a pharmaceutically acceptable carrier.
- suitable formulations include aqueous and non-aqueous sterile injection solutions which can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes which render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
- the formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a frozen or freeze-dried (lyophilized) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use.
- Some exemplary ingredients are SDS in the range of in some embodiments 0.1 to 10 mg/ml, in some embodiments about 2.0 mg/ml; and/or mannitol or another sugar in the range of in some embodiments 10 to 100 mg/ml, in some embodiments about 30 mg/ml; and/or phosphate-buffered saline (PBS). Any other agents conventional in the art having regard to the type of formulation in question can be used.
- the carrier is pharmaceutically acceptable. In some embodiments the carrier is pharmaceutically acceptable for use in humans.
- compositions of the present disclosure can have a pH between 5.5 and 8.5, preferably between 6 and 8, and more preferably about 7.
- the pH can be maintained by the use of a buffer.
- the composition can be sterile and/or pyrogen free.
- the composition can be isotonic with respect to humans.
- Pharmaceutical compositions of the presently disclosed subject matter can be supplied in hermetically-sealed containers.
- compositions can include an effective amount of one or more antibodies as described herein.
- a pharmaceutical composition can comprise an amount that is sufficient to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic effect.
- Therapeutic effects also include reduction in physical symptoms.
- the precise effective amount for any particular subject will depend upon their size and health, the nature and extent of the condition, and therapeutics or combination of therapeutics selected for administration. The effective amount for a given situation is determined by routine experimentation as practiced by one of ordinary skill in the art.
- compositions of the invention can be administered in a variety of unit dosage forms depending upon the method of administration. Dosages for typical antibody pharmaceutical compositions are well known to those of skill in the art. Such dosages are typically advisory in nature and are adjusted depending on the particular therapeutic context or patient tolerance. The amount antibody adequate to accomplish this is defined as a “therapeutically effective dose.”
- the dosage schedule and amounts effective for this use, i.e., the “dosing regimen,” will depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient’s health, the patient’s physical status, age, pharmaceutical formulation and concentration of active agent, and the like. In calculating the dosage regimen for a patient, the mode of administration also is taken into consideration.
- the dosage regimen must also take into consideration the pharmacokinetics, i.e., the pharmaceutical composition’s rate of absorption, bioavailability, metabolism, clearance, and the like. See, e.g., the latest Remington’s; Egleton, Peptides 18: 1431-1439, 1997; Langer, Science 249: 1527-1533, 1990.
- kits e.g., bottles or vials
- the containers are glass or PETG containers.
- the brain cancer is a glioblastoma.
- the subject is administered a therapeutically effective amount of the composition.
- a therapeutically effective amount of a composition comprising an antibody contains about 0.05 to 1500 pg protein, preferably about 10 to 1000 pg protein, more preferably about 30 to 500 pg and most preferably about 40 to 300 pg, or any integer between these values.
- antibodies of the invention can be administered to a subject at a dose of about 0.1 pg to about 200 mg, e.g., from about 0.1 pg to about 5 pg, from about 5 pg to about 10 pg, from about 10 pg to about 25 pg, from about 25 pg to about 50 pg, from about 50 pg to about 100 pg, from about 100 pg to about 500 pg, from about 500 pg to about 1 mg, from about 1 mg to about 2 mg, with optional boosters given at, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, two months, three months, 6 months and/or a year later.
- the specific dose level for any particular patient depends upon a variety of factors including the activity of the specific antibody employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- Routes of administration include, but are not limited to, oral, topical, subcutaneous, intramuscular, intravenous, subcutaneous, intradermal, transdermal and subdermal.
- the volume per dose is preferably about 0.001 to 10 ml, more preferably about 0.01 to 5 ml, and most preferably about 0.1 to 3 ml.
- Compositions can be administered in a single dose treatment or in multiple dose treatments on a schedule and over a time period appropriate to the age, weight and condition of the subject, the particular antibody formulation used, and the route of administration.
- kits comprising the containers comprising the antibodies and instructions for use.
- the containers have a label.
- Suitable containers include, for example, bottles, vials, and test tubes.
- the containers are formed from glass or PETG.
- the container holds a composition which includes the herein provided antibodies that is effective for therapeutic applications.
- the label on the container indicates that the composition is used for a particular therapy or non-therapeutic application, and can also indicate directions for either in vivo or in vitro use.
- the first drug substance (DS) antibody lot was contained in either (i) Wheaton (#223739) clear glass serum bottles with 20mm crimp top finish (10ml size) (low-alkali borosilicate molded glass) at a concentration of lOmg/ml concentration (approximately 4.5ml volume) or (ii) in clear PETG serum vial (#l-0456-81P; ThermoFisher Scientific) lined continuous thread closure (5ml size) at a concentration of lOmg/ml (approximately 4ml volume).
- the second DS antibody lot was contained in Nalgene cryogenic vials (#5000-1020) (1.5ml size polypropylene (PP) screwtop vial) at a concentration of 9.9mg/ml concentration (1ml volume).
- the third antibody lot and reference standard used for potency assay is 9.72mg/ml concentration (4ml volume) in PETG serum vial (# 1-0456-8 IP; ThermoFisher Scientific) lined continuous thread closure (5ml size; polyethylene terephthalate G (PETG)).
- the potency of the second antibody lot stored in the PP cryovial was compared to the first antibody lot stored in the clear PETG serum vial.
- the results in Figure 1 show significant difference in potency between the drug substance (DS) stored in PP cryovial versus PETG serum vial.
- the EC50 for the clinical DS from PETG vial was 9.6ug/ml while the EC50 for the PP cryovial was 20ug/ml.
- the potency for the clinical DS lot stored in PETG serum vial (9.6ug/ml) is similar to the potency for the clinical DS lot contained in glass serum containers (8.25ug/ml). This result suggests that the difference in EC50 values between clinical drug substance and clinical drug product is a result of storage in different containers.
- the clinical DS lot stored in PP cryovials shows weak potency and may not be representative of the drug product material potency stored in glass serum containers.
- the potency of binding assay was performed to compare the third antibody D S lot and reference standard stored in PP cryovial and stored in PETG serum vial.
- ELISA binding assay was performed on 3 separate third antibody DS lots from PP cryovials with a third antibody DS lot from PETG serum vial.
- the results of Figure 2 show that the DS lots stored in PP cryovials did not show the same potency as that stored in PETG serum vial.
- the PP cryovial stored DS lots had significantly lower binding (EC50 range 37ug/ml to 40 ug/ml) compared to the DS lot from the PETG serum vial (EC50 of 1 lug/ml).
- the binding ELISA assay compared clinical DS lots stored in PP cryovial with clinical DS lots stored in PETG serum vials. There was significant difference in potency between these samples.
- the EC50 value for the DS stored in PETG serum vial was similar to that reported for the clinical DS lot in glass containers and the Lot DS reference standard used for previous binding assays.
- Both the clinical DS stored in PP cryovials and the reference standard DS stored in PP cryovials is not representative of the drug product material (stored in glass serum vials) with respect to potency.
- both the clinical DS and toxicology DS stored in PETG serum vials shows EC50 values similar to the drug product material and is representative of the drug product with respect to potency.
- the storage conditions and formulations for the antibodies were tested. It was determined that product storage at 5°C results in degradation of the antibody. Storage at temperature ⁇ -60°C over 3 freeze-thaw cycles did not result in degradation. It is recommended/documented that this antibody be stored at temperatures below -60°C for long-term storage. Further, the preferred concentration and formulation of the antibody in clinical product vials were determined to be approximately lOmg/ml in lOmM Sodium phosphate, 150mM Sodium chloride pH7.0 (Phosphate-buffered saline (PBS)).
- PBS Phosphate-buffered saline
- Example 2 Pritumumab Binds Specifically To Cell Surface Of Glioma Cells And Shows Specificity For Vimentin.
- pritumumab binds the surface of glioma cells
- an assay was performed to determine if pritumumab can be competed away with recombinant human vimentin.
- the rationale of the experiment is to further demonstrate specificity of pritumumab antibody for extracellular vimentin.
- Figures 1 and 2 show the results of flow cytometry experiments. Table 1 summarizes the binding competition experiment. Incubating 160nM pritumumab with 45nM recombinant vimentin does not outcompete U251 cells for binding. However, incubating 160nM pritumumab with 2.5 molar excess recombinant vimentin (450nM) can prevent pritumumab binding to the U251 cell surface.
- Pritumumab for vimentin was employed to measure the antibody binding to human vimentin. Binding experiments were performed on Octet HTX at 25°C. Pritumumab (10 ug/ml) was loaded onto Anti-Human-Fc (AHC) biosensors. Loaded sensors were dipped into a serial of antigen dilutions (recombinant human vimentin) (300 nM start, 1:3 down, 7 points). Kinetic constants were calculated using a monovalent (1 : 1) model. The affinity of binding of the antibody, pritumumab, to vimentin was determined to be 7.55E-9M.
- the objective of this example was to determine if Pritumumab human monoclonal antibody stains central nervous system (CNS) neoplasms, particularly glioblastoma multifore and astrocytomas. These are the most common and aggressive primary CNS malignancies. To that end, immunohistochemical stains were performed on 80 human tissue cores. Seventy cores were from patients with glioblastomas and astrocytomas while 10 were from normal brains.
- CNS central nervous system
- the TMA cores were scanned using an Aperio ST Turbo scanner and links to the images made available for histomorphologic examination and scoring. The viewing software is proprietary to HistoWiz.
- the TMA cores are from human brain (CNS) tissue, and consist of examples of glioblastoma, astrocytomas, and normal cerebrum. The human glioblastoma TMA cores all show either nuclear or cytoplasmic positivity.
- pritumumab demonstrated positivity in all of the astrocytomas and glioblastomas. There is variability of stain intensity from case to case. The predominate localization is nuclear. Cytoplasmic staining is usually weak or absent but one case demonstrated strong cytoplasmic staining.
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Non-Patent Citations (4)
Title |
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GLASSY ET AL.: "Summary analysis of the pre-clinical and clinical results of brain tumor patients treated with pritumumab", HUM ANTIBODIES, vol. 18, no. 4, 2009, pages 127 - 37, XP055518853, DOI: 10.3233/HAB-2009-0209 * |
GUPTA ET AL.: "Human hybridoma and recombinant Pritumumab antibodies for treatment of human solid tumors", J IMMUNOTHER CANCER, vol. 2, no. 3, 2014, pages P149, XP021202457, DOI: 10.1186/2051-1426-2-S3-P149 * |
STFINMFT7 ET AL.: "Two Domains of Vimentin Are Expressed on the Surface of Lymph Node, Bone and Brain Metastatic Prostate Cancer Lines along with the Putative Stem Cell Marker Proteins CD 44 and CD 133", CANCERS, vol. 3, no. 3, 2011, Basel, pages 2870 - 2885, XP055300291, DOI: 10.3390/cancers3032870 * |
TICA JURE, BRADBURY ELIZABETH, DIDANGELOS ATHANASIOS: "Combined Transcriptomics, Proteomics and Bioinformatics Identify Drug Targets in Spinal Cord Injury", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 19, no. 5, pages 1461, XP093066709, DOI: 10.3390/ijms19051461 * |
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