Mutated anti-cd22 antibodies and immunoconjugates

Details Mutated anti-cd22 antibodies and immunoconjugates Mutated anti-cd22 antibodies and immunoconjugates

C - Chemistry, Metallurgy

07

K

C07K 16/28 (2006.01) A61K 39/395 (2006.01) A61K 47/48 (2006.01) C07K 14/21 (2006.01) C07K 19/00 (2006.01) C12N 15/13 (2006.01) C12N 15/62 (2006.01)

Patent

CA 2547165

Recombinant immunotoxins are fusion proteins composed of the Fv domains of antibodies fused to bacterial or plant toxins. RFB4 (Fv)-PE38 is an immunotoxin that targets CD22 expressed on B cells and B cell malignancies. The present invention provides antibodies and antibody fragments that have improved ability to bind the CD22 antigen compared to RFB4. Immunotoxins made with the antibodies and antibody fragments of the invention have improved cytotoxicity to CD22-expressing cancer cells. Compositions that incorporate these antibodies into chimeric immunotoxin molecules that can be used in medicaments and methods for inhibiting the growth and proliferation of such cancers. Additionally, the invention provides a method of increasing the cytotoxicity of forms of Pseudomonas exotoxin A ("PE") with the mutation of a single amino acid, as well as compositions of such mutated PEs, nucleic acids encoding them, and methods for using the mutated PEs.

Les immunotoxines recombinées sont des protéines de fusion composées de domaines Fv d'anticorps fusionnés à des toxines bactériennes ou végétales. RFB4 (Fv)-PE38 est une immunotoxine qui cible les CD22 exprimés sur des lymphocytes B et des tumeurs malignes développées par les lymphocytes B. L'invention concerne des anticorps et des fragments d'anticorps qui présentent une capacité améliorée de liaison à l'antigène CD22 en comparaison avec la RFB4. Des immunotoxines obtenues au moyen des anticorps et des fragments d'anticorps de l'invention présentent une cytotoxicité améliorée envers les cellules cancéreuses exprimant les CD22. L'invention concerne également des compositions qui comprennent ces anticorps dans des molécules d'immunotoxine chimères pouvant être utilisées dans des médicaments ainsi que des procédés permettant d'inhiber le développement et la prolifération desdits cancers. L'invention concerne en outre un procédé permettant d'améliorer la cytotoxicité de formes d'exotoxine A de Pseudomonas (<= PE >=) par mutation d'un seul acide aminé, ainsi que des compositions comprenant lesdits PE mutés, des acides nucléiques codant ceux-ci, et des procédés d'utilisation desdits PE mutés.

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