WO2007112047A2 - Formulations contenant des immunotoxines ciblées sur l'antigène de cellules mésothéliennes - Google Patents

Formulations contenant des immunotoxines ciblées sur l'antigène de cellules mésothéliennes Download PDF

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Publication number
WO2007112047A2
WO2007112047A2 PCT/US2007/007342 US2007007342W WO2007112047A2 WO 2007112047 A2 WO2007112047 A2 WO 2007112047A2 US 2007007342 W US2007007342 W US 2007007342W WO 2007112047 A2 WO2007112047 A2 WO 2007112047A2
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Prior art keywords
immunotoxin
sslp
formulation
concentration
buffer
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PCT/US2007/007342
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English (en)
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WO2007112047A3 (fr
Inventor
Stephen Youngster
Qing-Hong Dai
Diane Change
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Enzon Pharmaceuticals, Inc.
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Publication of WO2007112047A2 publication Critical patent/WO2007112047A2/fr
Publication of WO2007112047A3 publication Critical patent/WO2007112047A3/fr

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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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/55—Fusion polypeptide containing a fusion with a toxin, e.g. diphteria toxin

Definitions

  • the invention relates to improved formulations containing immunotoxins targeted to the mesothelin tumor cell antigen.
  • the invention also relates to formulations having improved shelf life and storage requirements.
  • SSlP is a recombinant immunotoxin consisting of a portion of Pseudomonas exotoxin A fused to the Fv region of an antibody directed towards mesothelin.
  • the exotoxin can shut down protein synthesis with high efficiency, thereby causing cell death.
  • Mesothelin is expressed in various cancers and mesotheliomas in greater quantities than in normal cells. Therefore, the antibody region of SSIP may be capable of delivering the toxin to these cells expressing mesothelin and SSlP may prove useful as an anticancer agent.
  • U.S. Patent No. 6,809,184 incorporated by reference herein, describes antibodies and antibody fragments that bind to mesothelin, a tumor antigen specific to ovarian cancers, mesotheliomas and several other types of human cancers, as well as recombinant immunotoxins based on fusions of a truncated PE and anti- mesothelin binding proteins.
  • an anti-mesothelin-PE immunotoxin engineered as a single-chain antigen-binding protein has been shown to have particularly desirable anticancer properties, especially when polymer conjugated, as described by PCT/US 05/45177 incorporated by reference herein.
  • aqueous SS lP immunotoxin formulations comprising a) from about 15 to about 40 mg/ ml SS IP immunotoxin; b) from about 5 to about 30 mM of a histidine buffer; c) from about 3 to about 5 mg/ml mannitol; d) from about 0.9 to about 1.1 mg/ml sucrose; and e) from about 0.025 to about 0.075 mg/ml of a polyoxyethylene sorbitan fatty acid ester surfactant.
  • Tween 20 Such as Tween 20.
  • aqueous SS l P immunotoxin formulations in accordance with this aspect of the invention are such that the IC 50 of the SS lP immunotoxin included therein against A431K5 cells in a cytotoxicity assay is less than about 1 ng/ml after 6 months at about 4°C and less than about 1 ng/ml after 6 months at about 25°C.
  • lyophilized SS lP immunotoxin formulations having improved stability and shelf life qualities.
  • compositions are made by lyophilizing a liquid containing: a) from about 15 to about 40 mg/ ml SS lP immunotoxin; b) from about 5 to about 30 ⁇ mol of a buffer comprising histidine, phosphate or a mixture thereof; c) from about 3 to about 5 mg/ml mannitol; d) from about 0.9 to about 1.1 mg/ml sucrose; and e) from about 0.025 to about 0.075 mg/ml of a polyoxyethylene sorbitan fatty acid ester surfactant.
  • Figures Ia and Ib are SEC HPLC profiles of SSlP ⁇ detection at 220 nm), stored in Histidine formulation, pH 7.0, at 4°C as a liquid formulation according to Example 1.
  • Figures 2a and 2b are comparative SEC HPLC profiles of SSlP (detection at 220 nm), stored in Phosphate formulation, pH 7.4, at 25°C in a comparative liquid formulation discussed in Comparative Example 1.
  • Figure 3 is a stability profile of SSlP in a lyophilized formulation monitored by SEC-HPLC corresponding to Example 3.
  • aqueous SS lP immunotoxin formulation includes: a) from about 15 to about 40 mg/ ml SSlP immunotoxin; b) from about 5 to about 30 mM of a histidine buffer; c) from about 3 to about 5 mg/ml mannitol; d) from about 0.9 to about 1.1 mg/ml sucrose; and e) from about 0.025 to about 0.075 mg/ml of a polyoxyethylene sorbitan fatty acid ester surfactant.
  • the preferred PE immunotoxin is SSlP as described herein, that is an dsFv PE immunotoxin formed by disulfide linkage of an SS 1-PE38 VH with an SS I VL peptide.
  • SS lP is a modification of the PE immunotoxin described by FIG. 1 of U.S. Patent No. 6,809, 184 (the ' 184 patent), incorporated by reference herein.
  • the SSV L CDR3 sequence is QQWSGYPLT (SEQ ID NO: 3).
  • the SS IVL CDR3 sequence of the immunotoxin described herein is QQWSKHPLT (SEQ ID NO: 4).
  • the complete SS 1 -PE38VH polypeptide sequence is that of SEQ ID NO: 5, that is encoded by the polynucleotide of SEQ ID NO: 6.
  • the complete SS IVL polypeptide sequence is that of SEQ ID NO: 7 , that is encoded by the polynucleotide of SEQ ID NO: 8.
  • the SSlP immunotoxin was constructed as a disulf ⁇ de-Iinked (“ds”) dimer. Each of the two components was separately expressed, isolated and renatured under conditions promoting ds dimer formation.
  • the anti-mesothelin heavy chain variable domain (“SS1-PE38V£ [ ”) was expressed in culture by BL21(DE3) host cells containing a pPDC7-4cm plasmid (FIG. 1; SEQ ID NO:2). This is the BL21(DE3)/pPSC7-4cm cell line.
  • the DNA molecule encoding the SS 1 -PE38VJJ polypeptide is according to SEQ ID NO: 6, and the SS l-PE38Vfj polypeptide sequence is as follows.
  • WGQGTTVTVSS 120 kasggpeggslaaltahqachlpletftrhrqprgweqleqcgypvqrlvalylaarlsw 180 nqvdqvirnalaspgsggdlgeaireqpeqarlaltlaaaeserfvrqgtgndeagaang 240 padsgdallernyptgaeflgdggdvsfstrgtqnwtverllqahrqleergyvfvgyhg 300.
  • SEQ ID NO: 5 Residues representing the Vfj domain are in UPPER case, the PE38 domains are in lower case.
  • a serine at position 45 of SEQ ID NO:5 has been changed to cysteine (underlined) to provide a site for the formation of a disufide bond to link with the separately produced VL.
  • the artisan will note that the replaced serine is actually designated as position 44 of the VJJ domain, based on
  • Plasmid pPSC7-7 plasmid (SEQ ID NO: 1) encodes the V L chain.
  • the V L polypeptide is encoded by a DNA molecule having a sequence according to SEQ ID NO: 8, and the VL polypeptide has the following sequence.
  • the BL21(DE3) E. coli strain carrying the plasmid expression vector containing cDNA of SSl-PE38Vj-[ was grown at 37° C, in Superbroth medium supplemented with kanamycin (lO ⁇ g/mi) and chloramphenicol (25 ⁇ g/ml) in batch culture in a 5L fermenter with 4.5L of medium for 5-6 hours until the density reached an OD ⁇ oo value of 5-8. Cells were then induced with 5 mM IPTG for 1.5 hours.
  • coli strain carrying expression vector containing cDNA of SS I-VL was grown at 7 0 C, in Superbroth medium supplemented with kanamycin (lO ⁇ g/ml) and chloramphenicol (25 ⁇ g/ml) in batch culture in a 5L fermenter with 4.5L of medium for 15-16 hours until the density reached an ODtoo value of 10-15. Cells were then induced with 5 mM IPTG for 1.5 hours. Grown cells containing the expressed SSIVL were harvested by centrifugation in a
  • Beckman centrifuge (model Avanti J-20I, Fullerton, CA) using a JLA8.1000 rotor for 20 minutes at 4 0 C at 7000 rpm.
  • a typical yield was 24-28g (wet weight) of cells per liter of culture medium.
  • SSl(dsFv)-PE38 was expressed in E. Coli host cells cultured as described above and purified by the following method. 1. Reagents and Buffers
  • the following reagents were employed in the purification of the SSlP immunotoxin from cultured host cells.
  • Lysozyme dithioerythritol (DTE); glutathione, oxidized form (GSSG); L- arginine-HCl; Triton X-100; urea; 0.1 N, IN NaOH.
  • the following buffers were employed in the purification of the SSlP immunotoxin from cultured host cells.
  • the refolding buffer was prepared as follows. The pH was adjusted to 10.5 with 10 N NaOH, the temperature was equilibrated to 4°C, and 0.9 mM GSSG (Glutathione, oxidized form) (551 mg/L) was added before the refolding.
  • the bottles were incubated for 60 mm at room temperature with intermittent shaking.
  • the settled pellet material was resuspended using a tissuemizer.
  • a tissuemizer was used to break up DNA mats, if present and then, the samples were centrifuged at 13000 rpm for 50 min at 4 0 C. 10. The pellets were then completely resuspended in TE 50/20 buffer, to which 20 ml of 25% Triton X-100 was added. 1 1. The samples were then centrifuged at 13000 rpm for 50 mi ⁇ at 4 0 C.
  • Steps 10-1 1 were repeated three times.
  • IB wet inclusion body
  • tissuemizer was used to resuspend the inclusion bodies. 3. The suspended IB samples were then incubated overnight at room temp.
  • the protein concentration was determined using the Pierce Coomassie Blue Plus assay (modified Bradford). The same final concentration of guanidine was used for the reference standard protein (BSA), and for the IB protein. The inclusion body solution was then 20-fold diluted with the solubilization solution, then the protein concentration assay was conducted.
  • the inclusion bodies were stored at -80 0 C, if not used right away.
  • the inclusion bodies of V L and V ⁇ -PE38 were then mixed together in a weight ratio of 1:2. f.
  • the inclusion body mixture was then 100-fold diluted with the refolding buffer.
  • g. The refolding solution was then incubated at 4°C for 36-42 hours without stirring. 5.
  • Concentration and Dialysis a. The pH of the refolding solution was adjusted down to 8.5. Then the refolding solution was 10-fold concentrated using Areicon H1P39043 hollow-fiber cartridges that were cleaned with 0.1 N NaOH, then washed with plenty of MiIH Q water to neutral pH.
  • the refolding solution was dialyzed against 20 mM Tris-HCl, pH 7.4 containing 0.1 M urea using the same cartridges.
  • the column was washed with 5-bed volume of 0.1 M NaCl in buffer A. The column was then eluted with 4-bed volume of 0.3 M NaCl in buffer A. b. The fractions were analyzed by SDS-PAGE and pooled in the first major peak. c. A Mono-Q column was treated the same way as was for the Q- Sepharose column. The pooled Q-Sepharose fractions were 5-fold diluted with buffer A and loaded on the column. The protein was then eluted with a NaCl gradient (0.1-0.3 M) in buffer A (20 bed volume).
  • fractions contain SSl (dsFv)-PE38, but only the fractions of the major peak have high activity, The major peak is separated by a narrow cliff.
  • One fraction was collected before the cliff and most of the fractions after the cliff, except the edge of the major peak, (fraction size is one half of the bed volume) d.
  • the pooled Mono Q fractions were 5-fold diluted and reloaded onto a smaller Mono Q column, then eluted with 0.5 M NaCl in buffer A.
  • e. AU of the fractions containing protein were pooled and loaded onto a Superalex 200 column previously washed with 0.1 N NaOH and equilibrated with PBS. The column was eluted with PBS.
  • Major peak fractions were pooled and protein concentration determined. The concentration was then adjusted to 1 mg/ml. Aliquots were prepared and frozen at-80 0 C.
  • SS lP protein Activity of the above-obtained SS lP protein was confirmed by a cytotoxicity assay using 15,000 cells/well. A431K5 cells were seeded in a 96-well plate. Samples of either native SSlP or of PEG-conjugates of SSlP were added to the cells the next day at different concentrations. Tritiated leucine was added 20 hours after addition of the SSIP/PEG-conjugates and incubated at 37 0 C for 2 hours. The IC50 value was around 0.8ng/mI.
  • the concentration of SSlP im " munotox.in in the formulation is from about 20 to about 30 mg/ml, and more preferably, about 25 mg/ml.
  • the aqueous formulations of the invention also include from about 5 to about 30 mM of a histidine buffer as described below, preferably the concentration of the buffer is from about 7.5 to about 15 mM, more preferably, the buffer concentration is about 10 mM.
  • the Histidine formulation preferably has a final pH of from about 6.8 to about 7.2. 2.
  • the preferred aqueous formulations include from about 3 to about 5 mg/ral mannitol, and preferably about 4 mg/ml.
  • the preferred aqueous formulations also include from about 0.9 to about
  • the preferred aqueous formulations include a surfactant which is preferably a polyoxyethylene sorbitan fatty acid ester surfactant such as a Tween, like Tween 20, (Surfact-Amps ® 20, Prod# 28320, available from Pierce).
  • a surfactant which is preferably a polyoxyethylene sorbitan fatty acid ester surfactant such as a Tween, like Tween 20, (Surfact-Amps ® 20, Prod# 28320, available from Pierce).
  • Tween polyoxyethylene sorbitan fatty acid ester surfactant
  • Other alternative surfactants of this class will be apparent to those of ordinary skill.
  • the surfactant is included in amounts from about 0.025 to about 0.075 mg/ml with amounts of about 0.05mg/ml being preferred.
  • a particularly preferred aqueous SS lP immunotoxin formulation having improved shelf life has the following characteristics: a) the SSlP immunotoxin concentration is from about 20 to about 30mg/ml; b) the mannitol concentration is about 40 mg/ml; c) the sucrose concentration is 1.0 mg/ml; d) the surfactant is Tween 20, present in a concentration of about 0.05 mg/ml; and e) the buffer is a 10 mM histidine buffer. The final pH of the Histidine formulation is 7.0.
  • the aqueous SS lP immunotoxin formulations of the invention are easy to store and transport.
  • the formulations can be kept at temperatures which are commonly found in commercial settings, including refrigeration and room temperature, for extended periods of time without significant loss of potency.
  • the data available suggests that the formulations have an IC 50 of about 1 ng/ml after 6 months at about 4°C against A431K5 cells in a cytotoxicity assay. Similar results are possible even after storage for 6 months at about 25°C.
  • lyophilized SSlP formulations which also have the property of extended shelf life and the ability to maintain potency of the immunotoxin for extended periods.
  • the lyophilization process includes three steps, freezing, primary drying and secondary drying.
  • the requirements include long-term stability, • short reconstitution time and elegant cake appearance, etc.
  • some preferred lyophilized SSlP immunotoxin formulations are made from aqueous SSlP formulations, including those described above.
  • the lyophilized powders can therefore be made from liquid formulations containing: a) from about 15 to about 40 mg/ ml SSlP immunotoxin; b) from about 5 to about 30 mM of a buffer comprising histidine, phosphate or a mixture thereof; c) from about 3 to about 5 mg/ml mannitol; d) from about 0.9 to about 1.1 mg/m] sucrose; and e) from about 0.025 to about 0.075 mg/ml of a polyoxyethylene sorbitan fatty acid ester surfactant.
  • the buffer formulations included as part of the invention are prepared using techniques well known to those of ordinary skill. Sufficient quantities are made upon need according to the following:
  • the weights of the ingredients for the lyophilized Histidine buffer formulation are as follows (for 1 mL of formulation):
  • the weights of the ingredients for the Iyophilized Phosphate buffer formulation are as follows (for 1 mL of formulation): 0.04 g of Mannitol 0.01 g of Sucrose 0.005 g ofTween 20
  • those which are included in this aspect of the invention can include not only the histidine buffer but also a phosphate buffer or a mixture of the two.
  • the concentration of SSlP immunotoxin is from about 20 to about 30 mg/ml, prior to lyophilization;
  • the concentration of the buffer is from about 7.5 to about 15 mM, prior to lyophilization;
  • the surfactant preferably Tween 20
  • the mannitol concentration is about 4 mg/ml and the sucrose concentration is about 1.0 mg/ml, prior to lyophilization.
  • one of the particularly preferred lyophilized SS lP immunotoxin formulations in accordance with the invention is based on a liquid formulation containing a) the SSlP immunotoxin concentration is from about 20 to about 30mg/ml; b) the mannitol concentration is about 40 mg/ml; c) the sucrose concentration is 1.0 mg/ml; d) the surfactant is Tween 20, present in a concentration of about 0.05 mg/ml; and e) the buffer is a 10 mM histidine buffer having a final pH of about 7.0, prior to lyophilization.
  • freeze drying techniques can be employed and that the procedure provided in the examples is merely for purposes of illustrating one preferred way of carrying out the invention.
  • the lyophilized SS lP immunotoxin formulations provide an SSlP immunotoxin after reconstitution which has an IC50 of about 1 ng/ml against A431K5 cells in a cytotoxicity assay after being stored for up to 6 months at about 4°C and even after 6 months of storage at about 25°C.
  • the formulations described herein can be used as part of therapeutic regimens in which SS lP immunotoxin is indicated.
  • the lyophilized versions of the inventive formulations can be reconstituted using standard techniques before administration.
  • GFC Purity Assay GFC was performed on an Agilent Technologies 1 100 HPLC system equipped with DAD and RI detectors. Data at both UV 220 nm and RI were acquired. A TosoHass G3000SWXL column (7.8 * 300mm) was used; phosphate-buffered saline (pH 7.4) was used as mobile phase; the flow rate was 0.5rnJL/min.
  • Protein concentration A Micro BCA protein assay was conducted to determine protein concentration. (Pierce Biotechnology, Rockford, IL 61 105, Lot# FD67447). Bioassay (ICJO). Samples were tested for their cytotoxic activity in A431K5 cells, the specification for potency is 0.1 to 2.0 ng/ml (protocol provided by Advanced BioScience Laboratories, Inc.). The specific cytotoxic activity of the immunotoxin, SSlP, was determined by inhibition of protein synthesis. The IC50 is the amount of immunotoxin required to inhibit protein synthesis by 50%.
  • the assay is based on the ability of living cells to convert the tetrazolium component of the Dye Solution into a formazan product, which is readily detected at 570 nm using a 96- well plate reader. A sample is considered fully active (100%) if its IC50 is in the range 0.1 to 2.0 ng/mL.
  • Histidine Buffer Solution and Phosphate buffer Solution were prepared in sufficient quantities according to the formulae described abov
  • Stability of the formulation is not conclusive evidence of a useful formulation as it is necessary to show that the immunotoxin maintains high levels of activity after extended periods of storage. Such tests were performed and the activity of the SSlP in the formulation was shown to be high even after up to 6 months at temperatures as high as 25°C.
  • Example 2 the procedure of Example 1 was repeated except that a phosphate formulation solution as described herein was used instead of the histidine formulation solution.
  • a freeze-dry cycle was developed which has provided white, elegant cakes, with a moisture level of approximately 2-3% based on Karl-Fisher test.
  • the instrument used was a LyoStar with LyoManager II Software, FTS System, from Kinetics Thermal Systems of Stone Ridge, New York. Generally speaking , the process comprised three steps, Step A. Freeze, Step B. Primary Dry and Step C. Secondary Dry.
  • Example 1 using the histidine buffer
  • Example 2 using the phosphate buffer
  • Step A Freeze — Product temperature is cooled to ensure it is completely frozen. Product was loaded at room temperature.
  • Step B Primary Dry - Sublimation of ice in the product to remove up to 90% of the moisture.
  • Step C Secondary Dry - Desorption of the tightly bound water in the product.
  • Lyophilization formulations for SSlP was tested for each of the two mentioned buffer systems, phosphate buffer and histidine-HCl.
  • the stability of SSlP was performed at 37°C, by SEC, IC50 etc. and the results are shown in Figure 3.
  • the HPLC profile by SEC confirms that the formulations are stable for at least 3 months at 37 0 C 3 at which time the study was stopped. It can be inferred from the accelerated data that such formulations will have stability extending for much longer periods when the formulation is stored at room temperature or in refrigerated conditions. Additional data in support of the inventive compositions has been compiled into Tables 5-8.
  • the data provides proof that the SSlP in the formulation containing phosphate buffer, is stable for at least 3 months at 37°C.
  • the phosphate buffer was not suitable for use in a extended storage formulation, it was indeed useful for inclusion in formulations which are undergoing lyophilization.
  • the lyophilized formulations of the proteinaceous drug SS lP have been developed which are stable for up to 6 months when stored under accelerated conditions of 25 0 C and up to -3 months at 37 0 C.
  • the stability of the formulations under the accelerated conditions correlate with the premise that the formulations will provide acceptable stability for SSIP for.a period of greater than one year at 4 0 C (and possibly 25°C) and, therefore, are useful as formulations for clinical product.
  • aqueous formulations of SSlP have also been developed which are stable for up to 6 months at both 4 0 C and 25°C.
  • the stability of the formulation at 25 0 C suggests that the formulation would maintain stability for more than one year at 4°C, and possibly at 25°C-
  • One preferred formulation corresponding to this aspect of the invention included 0.25 mg/mL SS lP, 0.05% Tween 20, 4% mannitol, 1% sucrose, and 10 mM histidine (pH 7.0).

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Abstract

La présente invention concerne des formulations liquides et lyophilisées d'immunotoxine SS1P présentant une grande stabilité et une durée de conservation prolongée. L'immunotoxine qu'elles contiennent possède des quantités très élevées d'activité résiduelle même après de longues périodes de stockage à 4 °C et même à la température ambiante.
PCT/US2007/007342 2006-03-24 2007-03-22 Formulations contenant des immunotoxines ciblées sur l'antigène de cellules mésothéliennes WO2007112047A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8911732B2 (en) 2010-12-20 2014-12-16 Genentech, Inc. Anti-mesothelin antibodies and immunoconjugates
EP3525822A4 (fr) * 2016-10-17 2020-05-06 Duke University Production d'immunotoxine d2c7-(scdsfv)-pe38kdel

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5917021A (en) * 1995-04-07 1999-06-29 Enzon, Inc. Stabilized monomeric protein compositions
WO2003009817A2 (fr) * 2001-07-25 2003-02-06 Protein Design Labs, Inc. Formulation pharmaceutique lyophilisee stable d'anticorps igg
US6809184B1 (en) * 1997-12-01 2004-10-26 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Antibodies, including FV molecules, and immunoconjugates having high binding affinity for mesothelin and methods for their use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5917021A (en) * 1995-04-07 1999-06-29 Enzon, Inc. Stabilized monomeric protein compositions
US6809184B1 (en) * 1997-12-01 2004-10-26 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Antibodies, including FV molecules, and immunoconjugates having high binding affinity for mesothelin and methods for their use
WO2003009817A2 (fr) * 2001-07-25 2003-02-06 Protein Design Labs, Inc. Formulation pharmaceutique lyophilisee stable d'anticorps igg

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8911732B2 (en) 2010-12-20 2014-12-16 Genentech, Inc. Anti-mesothelin antibodies and immunoconjugates
US9719996B2 (en) 2010-12-20 2017-08-01 Genentech, Inc. Anti-mesothelin antibodies and immunoconjugates
US10022452B2 (en) 2010-12-20 2018-07-17 Genentech, Inc. Anti-mesothelin antibodies and immunoconjugates
EP3525822A4 (fr) * 2016-10-17 2020-05-06 Duke University Production d'immunotoxine d2c7-(scdsfv)-pe38kdel
US11311628B2 (en) 2016-10-17 2022-04-26 Duke University Production of immunotoxin D2C7—(scdsFv)—PE38KDEL

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