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Seattle Genetics, Inc. Message Board

  • mauihope2000 mauihope2000 Nov 13, 2013 11:34 PM Flag

    SGN-CD33A...time to get excited before everyone else.

    Yes phase I has just begun and no results of any kind have been released but I'm excited now. SGN-CD33A is a whole new ADC animal. Like SGN30 and SGN40, SGN33 proved not to live up our hopes. Those early trials did prove the binding ability of the naked antibodies but not much anti-tumor activity. Adding the linker and chemo warhead proved a huge success when the ADC SGN-35 (Adcetris) was born. Now something even better is about to happen. A whole new kind of powerful, warhead is about to be released with even less collateral damage and it promises to change again how cancer is viewed and treated. The new warhead; pyrrolobezodiazepine (PBD) is DNA disrupter and has even fewer of the toxic sometimes deadly side effects of conventional systemic chemo.
    Here's a quote from last year's ASH:
    "Over the past four years, Seattle Genetics has selected and optimized specific PBD molecules combined with novel linkers for use in ADCs, and has conducted process development and scale-up activities to create robust synthetic GMP manufacturing processes for these PBD drug-linkers."
    AML is the perfect target. Most of the 14000 newly diagnosed are older than 50. About 80% relapse. Some qualify for high dose chemo and transplant but about 9000 die each year. It is a Huge unmet critical need that SGN-33A can meet. It is the kind of need that the FDA may be willing to fast track.
    I think it's going to be another success story.
    But that's just my worthless opinion. I've been wrong many times.

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    • Maui,
      Your insights are quite witty and very welcome. Not everyone may see it the same way all of the times but debate is how everyone gains more knowledge on issues that can ever do on their own. Collective thinking is invariably better than homogeneity.
      No need for you to qualify your insights/opinions as worthless. I assure you they are not.

    • Nice to see you so excited Maui, it's a nice change. I think with the following article you will see why the SGN75 trial was discontinued at phase 1. SG wants complete remissions and the PBD dimer appears to offer a much more potent attack on RCC and NHL. Even though the auristatin based ADC showed anti tumor activity, why push forward when it appears the pbd warhead will show better and more durable results for a very hard to treat tumor.
      Oops, I lost the link, I'll get it back.

      • 2 Replies to atpl1959
      • I'm thinking that they may have made a decision to not seek collaboration deals on PBD's and next generation linkers but instead keep that intellectual info in-house. My argument against a possible buy out was; there was no point since Sgen shared Intellectual property with anyone who wanted to use it. That may have changed. If I'm right I believe it makes SGEN a much more valuable buy out candidate.

      • It wouldn't let me post the link
        Here is the body of the srticle, you can google " A potent anti-CD 70 antibody-drug conjugate " and come up with it.

        A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody–drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.

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