Mar.Drugs 2014,12 263 tumor type likely to over-express(EGFR),are underway evaluating the safety,pharmacokinetics and efficacy of ABT-414,with a Phase lla expansion (NCT 01741727)at the maximum tolerated dose (MTD)where patients,accepted by invitation only,must have squamous cell Non-Small Cell Lung Cancer(NSCLC).The other trial at the Phase I level (NCTO1800695)is a study evaluating the safety and pharmacokinetics of ABT-414 in subjects with glioblastoma multiforme in combination with radiation plus temozolomide or temozolomide alone;the study is currently recruiting patients with this particular disease 3.4.3.PSMA-ADC(Phase II) This ADC is a fully human monoclonal antibody against prostate specific antigen that is coupled via the valine-citrulline dipeptide linker to mono-methylauristatin E(MMAE)and was designed to undergo release via proteolysis by human cathepsin B.The initial report demonstrating activity in prostate cancer cells and in xenografts was published in 2006 [53].This was followed in 2011 by a report showing expanded activity against androgen sensitive and insensitive cell lines in xenografts [54]. Since there are now reports of the PSMA antigen being present in glioblastoma multiforme,this ADC is in a Phase II trial currently recruiting patients with this specific cancer,in addition to the Phase I and II trials against prostate cancer.All three trials are listed as current in the NIH clinical trials database,but no trials are shown in the EU database at this time. 3.4.4.DCDT-2980S (Phase II) This ADC from Genentech (Roche,San Francisco,CA,USA)is a humanized IgGl antibody directed against the CD22 epitope linked to sulfhydryl groups on the antibody via a maleimide derivative.This derivative is the same as that used in Adcetris releasing monomethylauristatin E on protease cleavage.Since the CD22 epitope is not expressed in rodents.trials for safety were performed in cynomolgus monkeys and demonstrated adequate safety in primates plus efficacy in xenografts [55] Currently there is one Phase II trial recruiting and one active trial in the NIH clinical database and no records in the EU equivalent.These trials are in leukemias.not solid tumors. 34 5 DCDS-4501A (Phase I This is also from genentech/Roche.and is an adc with monomethylauristatin e linked to an anti-CD79b monoclonal.It is currently in the same Phase II trial as DCDT-2980S as an alternative treatment against follicular B cell lymphoma,and is also in an ongoing Phase I trial against various lymphomas in a dose escalation study.As with the earlier Roche agent(Section 3.4.4),no trials are listed in the EU database 3.4.6.Enfortumab vedotin(Phase I) This combination,a fully human IgGlk antibody linked to monomethyl auristatin E via a cleavable valine-citrulline linker is also known under the code names AGS-22MSE and AGS-22ME and is currently undergoing Phase I evaluation under the aegis of Agensys (Ashbum,VA,USA),Seattle Genetics and Astellas Pharma (Tokyo,Japan).It should be pointed out that Agensys isMar. Drugs 2014, 12 263 tumor type likely to over-express (EGFR), are underway evaluating the safety, pharmacokinetics and efficacy of ABT-414, with a Phase IIa expansion (NCT 01741727) at the maximum tolerated dose (MTD) where patients, accepted by invitation only, must have squamous cell Non-Small Cell Lung Cancer (NSCLC). The other trial at the Phase I level (NCT01800695) is a study evaluating the safety and pharmacokinetics of ABT-414 in subjects with glioblastoma multiforme in combination with radiation plus temozolomide or temozolomide alone; the study is currently recruiting patients with this particular disease. 3.4.3. PSMA-ADC (Phase II) This ADC is a fully human monoclonal antibody against prostate specific antigen that is coupled via the valine-citrulline dipeptide linker to mono-methylauristatin E (MMAE) and was designed to undergo release via proteolysis by human cathepsin B. The initial report demonstrating activity in prostate cancer cells and in xenografts was published in 2006 [53]. This was followed in 2011 by a report showing expanded activity against androgen sensitive and insensitive cell lines in xenografts [54]. Since there are now reports of the PSMA antigen being present in glioblastoma multiforme, this ADC is in a Phase II trial currently recruiting patients with this specific cancer, in addition to the Phase I and II trials against prostate cancer. All three trials are listed as current in the NIH clinical trials database, but no trials are shown in the EU database at this time. 3.4.4. DCDT-2980S (Phase II) This ADC from Genentech (Roche, San Francisco, CA, USA) is a humanized IgG1 antibody directed against the CD22 epitope linked to sulfhydryl groups on the antibody via a maleimide derivative. This derivative is the same as that used in Adcetris®, releasing monomethylauristatin E on protease cleavage. Since the CD22 epitope is not expressed in rodents, trials for safety were performed in cynomolgus monkeys and demonstrated adequate safety in primates plus efficacy in xenografts [55]. Currently there is one Phase II trial recruiting and one active trial in the NIH clinical database and no records in the EU equivalent. These trials are in leukemias, not solid tumors. 3.4.5. DCDS-4501A (Phase II) This is also from Genentech/Roche, and is an ADC with monomethylauristatin E linked to an anti-CD79b monoclonal. It is currently in the same Phase II trial as DCDT-2980S as an alternative treatment against follicular B cell lymphoma, and is also in an ongoing Phase I trial against various lymphomas in a dose escalation study. As with the earlier Roche agent (Section 3.4.4), no trials are listed in the EU database. 3.4.6. Enfortumab vedotin (Phase I) This combination, a fully human IgG1k antibody linked to monomethyl auristatin E via a cleavable valine-citrulline linker is also known under the code names AGS-22MSE and AGS-22ME and is currently undergoing Phase I evaluation under the aegis of Agensys (Ashburn, VA, USA), Seattle Genetics and Astellas Pharma (Tokyo, Japan). It should be pointed out that Agensys is