ES2643687T3 - Anticuerpos monoclonales humanos específicos de hLIGHT antagonistas - Google Patents

Anticuerpos monoclonales humanos específicos de hLIGHT antagonistas Download PDF

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ES2643687T3
ES2643687T3 ES12162958.8T ES12162958T ES2643687T3 ES 2643687 T3 ES2643687 T3 ES 2643687T3 ES 12162958 T ES12162958 T ES 12162958T ES 2643687 T3 ES2643687 T3 ES 2643687T3
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variable region
chain variable
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kappa
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Steven W. Granger
Shinichiro Kato
Carl F. Ware
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Kyowa Kirin Co Ltd
La Jolla Institute for Allergy and Immunology
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Kyowa Hakko Kirin Co Ltd
La Jolla Institute for Allergy and Immunology
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    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
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    • C07K2317/00—Immunoglobulins specific features
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    • C07K2317/00—Immunoglobulins specific features
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    • C07K2317/565—Complementarity determining region [CDR]
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

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Description

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28
Tabla 1
Antic.
VH CDR1 de VH CDR2 de VH CDR3 de VH VL CDR1 de VL CDR2 de VL CDR3 de VL
E1
(SEC ID nº 1) RFNMN(SEC ID nº 11) YISSSSYTIYYADSKVKG(SEC ID nº 12) SIAAFDY(SEC ID nº 13) (SEC ID nº 82,6*, 83) RASQGISSALA(SEC ID nº 84)RASQSVSSSYLT(SEC ID nº 26*)RASQSVSSSYLA(SEC ID nº 85) DASSLES(SEC ID nº 86)GASSRAT(SEC ID nº 37*)GASNRAT(SEC ID nº 87) QQFNSYRT(SEC ID nº 88)QQYGSSMYT(SEC ID nº 28*)QQYGSSPWT(SEC ID nº 89)
E13
(SEC ID nº 2) NAWMS(SEC ID nº 14) RIKSKIDGGTTDYAAPVKG(SEC ID nº 15) AMAGAFGF(SEC ID nº 16) (SEC ID nº 7) RASQSVSSSYLA(SEC ID nº 29) GASSRAT(SEC ID nº 30) QQYGSSPMYT(SEC ID nº 31)
E63
(SEC ID nº 3) SGGYYWS(SEC ID nº 17) YIYYSGSTNYNPSLKS(SEC ID nº 18) WITMFRGVGFDP(SEC ID nº 19) (SEC ID nº 8) RASQSIGSSLH(SEC ID nº 32) YASQSES(SEC ID nº 33) HQSSSLPLT(SEC ID nº 34)
F19
(SEC ID nº 4) GYNWH(SEC ID nº 20) EITHSGSTNYNPSLKS(SEC ID nº 21) EIAVAGTGYYGMDV(SEC ID nº 22) (SEC ID nº 90,9*, 91, 92) RVSQGISYLN(SEC ID nº 93)RASRGINSAFA(SEC ID nº 35*)RMSQGISSYLA(SEC ID nº 94RASQGVSSYLA(SEC ID nº 95) SASNLQS(SEC ID nº 96)DASSLES(SEC ID nº 36*)AASTLQS(SEC ID nº 97)DASWRAT(SEC ID nº 98) QRTJNAPPT(SEC ID nº 99)QQFNSYPLT(SEC ID nº 37*)QQYYSFPYT(SEC ID nº 100)QQRSNWHP(SEC ID nº 101)
F23
(SEC ID nº 5) GYYWN(SEC ID nº 23) EINQYNPSLKS(SEC ID nº 24) EIATADKGYYGLDV(SEC ID nº 25) (SEC ID nº 10) RASQGISSALA(SEC ID nº 38) DASSLES(SEC ID nº 39) QQFNSYPLT(SEC ID nº 40)
*secuencias preferidas de VL y de CDR1-3 de VL de E1 y F19.
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concentración de proteína a partir de la absorbancia a 280 nm. Secuencia de nucleótidos de un hLIGHT desde el codón de inicio (ATG) hasta la parada (TGA) (SEC ID nº 51):
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Secuencia de aminoácidos de un hLIGHT de longitud completa 240 aa (SEC ID nº 52):
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Secuencia de nucleótidos de un hLIGHT marcado con FLAG soluble (se muestran las secuencias líder de VCAM, seguido de las secuencias codificantes de FLAG en negrita) (SEC ID nº 53):
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67 Secuencia de aminoácidos de hLIGHT marcado con FLAG soluble 183 aa (FLAG en negrita) (SEC ID nº 54):
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Se transfectaron establemente células EL4 (ATCC nº TIB-39) con un retrovirus que contenía el ADNc codificante de hLIGHT de longitud completa para la generación de la línea celular EL4-HLIGHT.
Preparación de proteína de fusión de Fc: la clonación, expresión y purificación de las proteínas de fusión de receptor solubles que contenían la región Fc de la IgG1 humana y los dominios de unión a ligando del RLTβ humano y HVEM humano han sido descritas anteriormente (Rooney et al., Methods Enzymol. 322:345-63, 2000). Brevemente, se aislaron las regiones extracelulares de HVEM y RLTβ mediante reacciones en cadena de la polimerasa utilizando cebadores con sitios de endonucleasa de restricción incorporados y se ligaron en el mismo marco en el vector baculovirus pVL1392 (Pharmingen) que contenía la IgG1 de Fc humana. Se infectaron células de insecto Trichoplusia ni High-Five BTI-TN-5b1-4 (Tn5) (Invitrogen Corp.) con los baculovirus recombinantes RLTβ:Fc o HVEM:Fc para la producción de proteínas (ver purificación de anticuerpos y proteínas).
Ratones: se obtuvieron de Kirin Brewery Co., Ltd., Japón, ratones transcromosómicos humanos KM miceTM (documento nº WO 02/43478 y nº WO 02/092812, Ishida y Lonberg, IBC’s 11th Antibody Engineering Meeting, resumen, 2000; y Kataoka, IBC’s 13th Antibody Engineering Meeting, resumen, 2002) que eran portadores de fragmentos de cromosoma humano codificantes de la región de inmunoglobulina humana, y se alojaron en las instalaciones para animales de Gemini Science (La Jolla, CA). Una vista general de la tecnología de producción de anticuerpos humanos se describe en Lonberg y Huszar, Int. Rev. Immunol. 13:65-93, 1995. Los animales transgénicos con uno o más genes de inmunoglobulina humana (kappa o lambda) que no expresan inmunoglobulinas endógenas se describen en, por ejemplo, la patente US nº 5.939.598. Se describen métodos adicionales de producción de anticuerpos humanos y anticuerpos monoclonales humanos (ver, por ejemplo, los documentos nº WO 98/24893, nº WO 92/01047, nº WO 96/34096 y nº WO 93/33735, y las patentes US nº 5.413.923, 5.625.126; 5.633.425; 5.569.825, 5.661.016, 5.545.806, 5.814.318, 5.885.793, 5.916.771 y 5.939.598). El desarrollo de bovinos portadores de genes de inmunoglobulina humana, vacas TC, se describe en Ishida y Lonberg (ver Ishida, 11th Antibody Engineering Meeting, 2000; Kuroiwa et al., Nat. Genet. 36:775-80, 2004; Kuroiwa et al., Nat. Biotechnol. 20:889-94, 2002).
Inmunización: se mezcló proteína recombinante hLIGHT soluble marcada con FLAG con un volumen igual de adyuvante completo de Freund (ACF, Sigma) y se preparó una emulsión. Los ratones fueron inmunizados con 10 a 50 µg de proteína por vía subcutánea (s.c.) y recibieron un refuerzo s.c. de 10 a 20 µg de proteína emulsionada en adyuvante incompleto de Freund (AIF, Sigma) a intervalos de 2 a 3 semanas durante 2 a 3 refuerzos. Se administró una inyección intravenossa (i.v.) final de 10 µg de hLIGHT soluble marcado con FLAG sin adyuvante 3 días antes de la fusión.
Producción de hibrfidoma: los ratones que mostraban el título de anticuerpos específicos anti-IgG de hLIGHT más alto en su suero, según se determinó mediante ELISA de hLIGHT y FACS utilizando células EL4 transducidas con hLIGHT frente a células EL4 parentales, se seleccionaron para la producción de anticuerpo monoclonales. Se recolectaron los bazos y se fusionaron suspensiones de células individuales con la línea celular de mieloma SP2/O-Ag14 (ATCC, Manassas, VA) en una proporción 5:1 con polietilenglicol al 50% (Boehringer Mannheim, Indianapolis, IN). Las fusiones se sembraron en placas de fondo plano de 96 pocillos a una densidad óptima (en este caso 1x106/ml) en medio DMEM-10 completo (medio de Eagle modificado por Dulbecco con suero de feto bovino al 10% (FBS, Invitrogen, Corp.), aminoácidos no esenciales al 1%, Lglutamina 2 Mm, 100 U/ml de penicilina, 100 µg/ml de sulfato de estreptomicina (todos de BioWhittaker, Walkersville, MD), complemento HAT (Sigma) y factor de clonación de hibridoma al 10% (FCH, Biovaris, San Diego, CA) y se cultivaron a 37ºC en un incubador con 10% de CO2. Se cribaron aproximadamente 2.800 pocillos de 2 fusiones mediante ELISA par anticuerpos específicos de hLIGHT que contenía kappa humana. Los anticuerpos IgG anti-HLIGHT humanos se confirmaron mediante análisis de citometría de flujo utilizando células hLIGHT+EL4 frente a células EL4 parentales. Los pocillos positivos también se sometieron a ensayo para la actividad de bloqueo de receptores mediante incubación de medio de cultivo por agotamiento de hibridoma en bruto con células EL4-HLIGHT y tinción con HVEM:Fc o RLTβ:Fc semisaturante. Los pocillos positivos se expandieron y se sometieron a 3 a 5 rondas de clonación por dilución limitante, obteniendo anticuerpos monoclonales.
Purificación de anticuerpos y proteínas: para la purificación de anticuerpos, se cultivaron hibridomas en botellas de cultivo giratorias de 2 litros con 350 mililitros a 1 litro/botella o en un sistema Integra de 1 litro (INTEGRA Bioscience, Inc., Ijamsville, MD) con medio sin suero (SFM) para hibridoma (Invitrogen, Corp.) complementado
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expresión de IgG1 (IDEC Pharmaceuticals, San Diego, CA, N5KGA1-Val Lark (un vector de modificado de N5KG1 (patente US nº 6.001.358)) que se predigirió con NheI y SalI (fragmento de ADN de 8,9 kilobases). La existencia de VH se analizó mediante digestión de restricción.
5 A continuación, los cebadores oligonucleótidos que contenían los sitios de reconocimiento de enzimas de restricción 5’ BglII y 3’ BsiWI se diseñaron para amplificar la región variable de la cadena ligera (VL) mediante PCR. Por ejemplo, tras la subclonación de VH de E63 indicada anteriormente, se insertó VL de E63 en el vector N5KG1-Val Lark-VH mediante la digestión del vector de ADN con BglII y BsiWI. A continuación, se aisló el fragmento de ADN de 9,1 kb. De manera similar al constructo de VH, se diseñó un juego de cebadores para la
10 PCR de VL que contuviese los sitios de reconocimiento para 5’BglI y 3’BsiWI. Estos cebadores, E63LF84 (SEC ID nº 62) y E63LR43 (SEC ID nº 63) fueron utilizados para amplificar VL a partir del ADN plasmídico mini-prep de pTopoE63VL. El producto de PCR se digirió con BglII y BsiWI y se aisló mediante electroforesis en gel de agarosa y purificación en gel. Este fragmento, que contenía E63VL, se ligó con el vector preparado de 9,1 kb con ADN ligasa de T4 y se utilizó para transformar células Top10 (Invitrogen). Se seleccionaron los transformantes
15 de E. coli positivos. Este vector de expresión, pG1K112E63 se purificó y la presencia de ambas regiones, E63VL y E63VH, se confirmó mediante análisis de restricción.
La generación de vectores para producir los anticuerpos recombinantes F23G1, E1G1 y F19G1 se llevó a cabo de esencialmente la misma manera que para E63G1. La amplificación por PCR de VH de F23 se llevó a cabo 20 utilizando F23HF86 (SEC ID nº 66) y F23HR55 (SEC ID nº 67). Los cebadores de amplificación de VL de F23 eran F23LF36 (SEC ID nº 68) y F23LR43 (SEC ID nº 69). La amplificación por PCR de VH de E1 se llevó a cabo utilizando E1HFSal1 (SEC ID nº 70) y E1HRNheI (SEC ID nº 71). La amplificación por PCR de E1VL kappa(A), E1VL kappa(B) y E1VL kappa(C) se llevó a cabo utilizando E1KF2+3BglII (SEC ID nº 74) emparejado con E1KR2BsiWI (SEC ID nº 75) o E1KR3BsiWI (SEC ID nº 76). La amplificación por PCR de VH de F19 se llevó a 25 cabo utilizando F19HFSalI (SEC ID nº 72) y F19HRNheI (SEC ID nº 73). La amplificación por PCR de F19L kappa(A) y F19L kappa(B) se llevó a cabo utilizando F19KR1+2BsiWI (SEC ID nº 77) y F19KF1+2+3BglII (SEC ID nº 79). La amplificación por PCR de F19L kappa(C) se llevó a cabo utilizando F19KR3BsiWI (SEC ID nº 78) y F19KF1+2+3BglII (SEC ID nº 79). Los vectores resultantes, pKLG1/F23, pKLG1/E1 y pKLG1/F19, también se confirmaron medinate digestió ncon enzimas de restricción y secuenciación. F19L kappa(D) no se amplificó por
30 PCR debido a un desplazamiento del marco de lectura, que se detectó medinate análisis de las escuencias, que produjo un segmento C-terminal del anticuerpo.
Secuencia de nucleótidos del ADNc de la región variable de cadena pesada (VH) de E63 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 43):
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Secuencia de nucleótidos del ADNc de la región variable de cadena ligera (VL) de E63 (entre el codón de inicio
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(ATG) y el final de la región variable) (SEC ID nº 48):
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Secuencia de nucleótidos de ADNc de la región variable de cadena pesada de F23 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 45):
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Secuencia de nucleótidos del ADNc de la región variable de cadena ligera kappa de F23 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 50):
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Secuencia de nucleótidos del ADNc de la región variable de cadena pesada de E1 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 41):
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Secuencia de nucleótidos del ADNc de la región variable de cadena ligera kappa de E1 región nº 1 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 102):
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Secuencia de nucleótidos del ADNc de la región variable de cadena ligera kappa de E1 región nº 2 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 46):
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10 Secuencia de nucleótidos del ADNc de la región variable de cadena ligera kappa de E1 región nº 3 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 103):
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15 Secuencia de nucleótidos del ADNc de la región variable de cadena pesada de E13 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 42):
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73
Secuencia de nucleótidos del ADNc de la región variable de cadena ligera kappa de E13 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 47):
imagen80
Secuencia de nucleótidos del ADNc de la región variable de cadena pesada de F19 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 44):
imagen81
Secuencia de nucleótidos del ADNc de la región variable de cadena ligera kappa de F19 región nº 1 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 104):
imagen82
Secuencia de nucleótidos del ADNc de la región variable de cadena ligera kappa de F19 región nº 2 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 49):
imagen83
Secuencia de nucleótidos del ADNc de la región variable de cadena kappa de F19 región nº 3 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 105):
74
imagen84
Secuencia de nucleótidos del ADNc de la región variable de cadena kappa de F19 región nº 4 (entre el codón de inicio (ATG) y el final de la región variable) (SEC ID nº 106):
imagen85
10 Secuencia de aminoácidos de la región variable de cadena pesada de E63 (secuencia líder (en negrita) y región variable) (SEC ID nº 3):
imagen86
15 Secuencia de aminoácidos de la región variable de cadena ligera de E63 (secuencia líder (en negrita) y región variable) (SEC ID nº 8):
imagen87
20 Secuencia de aminoácidos de la región variable de cadena pesada de F23 (secuencia líder (en negrita) y región variable) (SEC ID nº 5):
imagen88
25 Secuencia de aminoácidos de la región variable de cadena ligera kappa de F23 (secuencia líder (en negrita) y región variable) (SEC ID nº 10):
imagen89
30 Secuencia de aminoácidos de la región variable de cadena pesada de E1 (secuencia líder (en negrita) y región variable) (SEC ID nº 1):
imagen90
75
imagen91
Secuencia de aminoácidos de la región variable de cadena ligera kappa de E1 región nº 1 (E1kappa(A)) (secuencia líder (en negrita) y región variable) (SEC ID nº 82):
imagen92
Secuencia de aminoácidos de la región variable de cadena ligera kappa de E1 región nº 2 (E1kappa(B)) (secuencia líder (en negrita) y región variable) (SEC ID nº 6):
imagen93
Secuencia de aminoácidos de la región variable de cadena ligera kappa de E1 región nº 3 (E1kappa(C)) (secuencia líder (en negrita) y región variable) (SEC ID nº 83):
imagen94
Secuencia de aminoácidos de la región variable de cadena pesada de E13 (secuencia líder (en negrita) y región variable) (SEC ID nº 2):
imagen95
Secuencia de aminoácidos de la región variable de cadena ligera kappa de E13 (secuencia líder (en negrita) y región variable) (SEC ID nº 7):
imagen96
Secuencia de aminoácidos de la región variable de cadena pesada de F19 (secuencia líder (en negrita) y región variable) (SEC ID nº 4):
imagen97
Secuencia de aminoácidos de la región variable de cadena ligera kappa de F19 región nº 1 (F19kappa(A)) (secuencia líder (en negrita) y región variable) (SEC ID nº 90):
imagen98
76
Secuencia de aminoácidos de la región variable de cadena ligera kappa de F19 región nº 2 (F19kappa(B)) (secuencia líder (en negrita) y región variable) (SEC ID nº 9):
imagen99
Secuencia de aminoácidos de la región variable de cadena ligera kappa de F19 región nº 3 (F19kappa(C)) (secuencia líder (en negrita) y región variable) (SEC ID nº 91):
imagen100
Secuencia de aminoácidos de la región variable de cadena ligera kappa de F19 región nº 4 (F19kappa(D)) (secuencia líder (en negrita) y región variable) (SEC ID nº 92):
imagen101
Tabla 2: cebadores de ADN sintetizados
SEC ID nº
Nombre Secuencia 5' a 3' Longitud
55
RACEUPS5' CTAATACGACTCACTATAGGGC 22-mero
56
IgG1p TCTTGTCCACCTTGGTGTTGCTGGGCTTGTG 31-mero
57
HK5 AGGCACACAACAGACGCAGTTGCAGATTTC 30-mero
58
M13F GTAAAACGACGGCCAGTG 18-mero
59
M13R CAGGAAACAGCTATGAC 17-mero
60
E63HF85 AGAGAGAGAGGTCGACCACCATGAAACACCTGTGGTTCTTC 41-mero
61
E63HR38 GAGAGAGAGAGCTAGCTGAGGAGACGGTGACCAGGGT 37-mero
62
E63LF84 AGAGAGAGAGATCTCTCACCATGTCGCCATCACAACTCATTG 42-mero
63
E63LR43 AGAGAGAGAGCGTACGTTTGATCTCCACCTTGGTCCCTCC 40-mero
64
HH-2 GCTGGAGGGCACGGTCACCACGCTG 25-mero
65
HK-2 GTTGAAGCTCTTTGTGACGGGCGAGC 26-mero
66
F23HF86 AGAGAGAGAGGTCGACCACCATGGACCTCCTGCACAAGAAC 41-mero
67
F23HR55 AGAGAGAGAGGCTAGCTGAGGAGACGGTGACCGT 34-mero
68
F23LP36 AGAGAGAGAGATCTCTCACCATGGACATGAGGGTCCCCGCTC 42-mero
69
F23LR43 AGAGAGAGAGCGTACGTTTGATCTCCACCTTGGTCCCTCC 40-mero
70
E1HFSall AGAGAGAGAGGTCGACCACCATGGAGTTGGGGCTGTGCTGG 41-mero
71
E1HRNhel AGAGAGAGAGGCTAGCTGAGGAGACGGTGACCAGGGC 37-mero
72
F19HFSall AGAGAGAGAGGTCGACCACCATGAAACACCTGTGGTTCTTC 41-mero
73
F19HRNhel AGAGAGAGAGGCTAGCTGAGGAGACGGTGACCGTGGT 37-mero
74
E1KF2+3BglII AGAGAGAGAGATCTCTCACCATGGAAACCCCAGCGCAGCTTC 42-mero
75
E1KR2BsiWI AGAGAGAGAGCGTACGTTTGATCTCCAGCTTGGTCCCCTG 40-mero
76
E1KR3BsiWI AGAGAGAGAGCGTACGTTTGATTTCCACCTTGGTCCCTTG 40-mero
77
F19KR1+2BsiWI AGAGAGAGAGCGTACGTTTGRTCTCCACCTTGGTCCCTCC 40-mero
78
F19KR3BsiWI AGAGAGAGAGCGTACGTTTGATCTCCAGCTTGGTCCCCTG 40-mero
79
F19KF1+2+3BglII AGAGAGAGAGATCTCTCACCATGGACATGAGGGTCCCCGCTC 42-mero
Se describe KM mouseTM en, por ejemplo, Fishwild et al., Nat. Biotechnol. 14:845-51, 1996; Lonberg et al., Nat.
20 Biotechnol. 9:1117-1125, 2005; Tomizuka et al., Proc. Natl. Acad. Sci. USA 97:722-7, 2000; Tomizuka, Nat. Genet. 16:133-43, 1997. Debido a la naturaleza de KM mouseTM (por ejemplo, se ha integrado más de un gen de cadena kappa en el genoma murino al generar la cepa transgénica kappa) resultó posible disponer de más de un ADNc de cadena ligera kappa expresado a partir de un hibridoma clonal. Para determinar si ello era de esta manera, se secuenció un mínimo de diez clones de ADNc. En los casos en que se aislaba más de un ADNc de
25 anticuerpo de cadena ligera kappa (por ejemplo, E1 y F19), se generaron varios constructos que contenían las diversas parejas de ADNc de cadena pesada combinados con cada ADNc de kappa. Estos constructos de expresión se transfectaron en células 293F utilizando 293FECTIN (Invitrogen, San Diego, CA). A continuación,
77
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