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1Oncology, Bayer HealthCare AG.
Carbonic anhydrase 9 (CAIX, carbonic anhydrase 9) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia, and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ecto-domain of CAIX against the MorphoSys HUCAL Gold library of human Fabs. Highest affinity Fabs were converted to full length IgGs and subjected to further characterization based upon their avidity and selectivity for CAIX, their capacity to undergo internalization in CAIX expressing cell lines and their selective localization to CAIX positive human xenografted tumors when administered to mice as fluorescent-conjugates. Through this selection process, the 3ee9 monoclonal antibody was identified which upon conjugation to Monomethyl Auristatin E (MMAE) through a self-imolative enzyme-cleavable linker yielded the potent and selective CAIX antibody drug conjugate CAIX-ADC (BAY 79-4620). In preclinical human xenograft models in mice representing several tumor indications, BAY 79-4620 showed potent anti-tumor efficacy and in some models demonstrated partial and complete tumor shrinkage even following a single dose. The mechanism of action was shown by histology to involve the sequelae of events typical of anti-tubulin agents. Efficacy in murine preclinical models correlated semi-quantitatively with CAIX expression levels as determined by IHC and ELISA. These preclinical data collectively support the development of BAY 79-4620 for the treatment of cancer patients with CAIX over-expressing tumors.
es gibt auch noch viele andere interessante Publikationen. Mein Eindruck aus den letzten 10 Jahren Publikationstätigkeit zu Antikörpern ist, dass die Synergien der verschiedenen Studienergebnisse sich immer mehr verdichten und ein Durchbruch in verschiedenen Anwendungsbereichen bald stattfinden wird. Ich denke es wird nicht nur das ein oder andere einzelne Medikament sein, sondern eine ganze Generation von Medikamenten und Wirkprinzipien, bei denen Morphosys eine zentrale Position haben wird.
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