Mar.Drugs 2014.12 262 A relationship to marine sources for the "warhead endiyne molecule"was established when investigators at the Scripps Oceanographic Institution (La Jolla,CA.USA)showed the presence of endiyne cryptic clusters in marine bacteria of the genus Salinospora [40]. Adcetris is the product of extensive work by Seattle Genetics (Seattle,WA,USA),first in optimizing the vedotin warhead(10)and then developing the linkers that couple the antibody to the compound [41].Some of these,discussed later,are designed to release the warhead (vedotin)by simple hydrolysis of a linker bond,whereas others require the enzymatic digestion of the antibody. releasing the warhead plus appendages.It was approved by the FDA in 2011 and subsequently approval was given in the EU late in 2012 and launched in the UK in early 2013,all for CD30 positive leukemias.Full explanations of the methodologies used and the utility of this agent against a variety of lymphomas have been published in the last three vears and should be consulted by the interested reader [42-45].In addition,a recent report from Takeda(Osaka,Japan)shows the strategy that this company is adopting,including the further development of this agent [46]. Currently,this agent is in 37 trials mainly in the USA from Phase 0 to Phase IV where the latter trial is listed as recruiting on the NIH clinical trials site.Six more are listed in the EU clinical trials site covering Phase II to Phase IV 3.4.1.Glembatumumab Vedotin (Phase II) This is monomethvlauristatin E (MMAE)linked to a fully human monoclonal antibody CROll (an anti-CG56972)via a stable valine-citrulline dipeptide linker.It was targeted against patients with unresectable melanomas at stage III or IV who have failed one cytotoxic chemotherapy regimen and has expanded to include metastatic breast cancer as well.The combination has a variety of names during its early days including CDX-011.CR-011 and CR011-veMMAE,so searching for data can be a trifle challenging. The initial report of the use of this combination was given by investigators from CuraGen in 2006[47].followed by a report of xenograft activity in 2007 from the same group [4].The value of the monoclonal's target in triple negative breast cancer was described in 2010 by Rose et al.[49],with the corresponding details in melanoma described in 2012 by a group from the People's Republic of China [50].Currently three completed studies at the Phase I/II levels are reported in the NIH clinical trials database with one preliminary report of clinical activity in breast cancer patients [51]. 3.4.2.ABT-414 (Phase I-II) This is an antibody-drug conjugate (ADC)linking the anti-Epidermal Growth Factor Receptor (EGFR)antibody ABT-806 to another variation on auristatin;in this case,monomethylaurisatin F (Figure 2,11)is used in place of the"E"variant.The ADC was designed to bind to a unique epitope of EGFR that is usually not accessible when EGFR is expressed at physiological levels.However,the ADC binds when tumors express EGFRde2-7(EGFRvIII)and in other tumors with amplified EGFR or excessive EGFR activation under"normal wild-type conditions"[521. Abbvie (North Chicago,IL.USA),which is the renamed Abbott Pharmaceutical Division,recently instituted two human clinical trials as trials in mice using human wild-type EGFR-overexpressing tumors gave complete regressions and"cures"[52].Phase I studies where patients must have a solid Mar. Drugs 2014, 12 262 A relationship to marine sources for the “warhead endiyne molecule” was established when investigators at the Scripps Oceanographic Institution (La Jolla, CA, USA) showed the presence of endiyne cryptic clusters in marine bacteria of the genus Salinospora [40]. Adcetris® is the product of extensive work by Seattle Genetics (Seattle, WA, USA), first in optimizing the vedotin warhead (10) and then developing the linkers that couple the antibody to the compound [41]. Some of these, discussed later, are designed to release the warhead (vedotin) by simple hydrolysis of a linker bond, whereas others require the enzymatic digestion of the antibody, releasing the warhead plus appendages. It was approved by the FDA in 2011 and subsequently approval was given in the EU late in 2012 and launched in the UK in early 2013, all for CD30 positive leukemias. Full explanations of the methodologies used and the utility of this agent against a variety of lymphomas have been published in the last three years and should be consulted by the interested reader [42–45]. In addition, a recent report from Takeda (Osaka, Japan) shows the strategy that this company is adopting, including the further development of this agent [46]. Currently, this agent is in 37 trials mainly in the USA from Phase 0 to Phase IV where the latter trial is listed as recruiting on the NIH clinical trials site. Six more are listed in the EU clinical trials site covering Phase II to Phase IV. 3.4.1. Glembatumumab Vedotin (Phase II) This is monomethylauristatin E (MMAE) linked to a fully human monoclonal antibody CR011 (an anti-CG56972) via a stable valine-citrulline dipeptide linker. It was targeted against patients with unresectable melanomas at stage III or IV who have failed one cytotoxic chemotherapy regimen and has expanded to include metastatic breast cancer as well. The combination has a variety of names during its early days including CDX-011, CR-011 and CR011-vcMMAE, so searching for data can be a trifle challenging. The initial report of the use of this combination was given by investigators from CuraGen in 2006 [47], followed by a report of xenograft activity in 2007 from the same group [48]. The value of the monoclonal’s target in triple negative breast cancer was described in 2010 by Rose et al. [49], with the corresponding details in melanoma described in 2012 by a group from the People’s Republic of China [50]. Currently three completed studies at the Phase I/II levels are reported in the NIH clinical trials database with one preliminary report of clinical activity in breast cancer patients [51]. 3.4.2. ABT-414 (Phase I–II) This is an antibody-drug conjugate (ADC) linking the anti-Epidermal Growth Factor Receptor (EGFR) antibody ABT-806 to another variation on auristatin; in this case, monomethylaurisatin F (Figure 2, 11) is used in place of the “E” variant. The ADC was designed to bind to a unique epitope of EGFR that is usually not accessible when EGFR is expressed at physiological levels. However, the ADC binds when tumors express EGFRde2-7 (EGFRvIII) and in other tumors with amplified EGFR or excessive EGFR activation under “normal wild-type conditions” [52]. Abbvie (North Chicago, IL, USA), which is the renamed Abbott Pharmaceutical Division, recently instituted two human clinical trials as trials in mice using human wild-type EGFR-overexpressing tumors gave complete regressions and “cures” [52]. Phase I studies where patients must have a solid