Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products:  Microtubule Antagonists

  • Maytansinoids and Auristatins:

    • Overview:

      • Antibody drug conjugates (ADC) were initially attempted using the anticancer drug doxorubicin.¹⁰ 

        • This approach attempted improved tissue localization, although more potent drugs appeared necessary.

        • Antibody drug conjugates, as an approach, advanced concurrent with the development of newer, highly potent anticancer agents including calicheamicins, auristatins, and maytansinoids.¹⁰  

          • Maytansine¹²

      • The basic idea involved delivering the cytotoxic drug to antigen-expressing tumor cells taking advantage of antibody specificity. ADCs are comprised using three components: an antibody, a linker and the anticancer drug.¹¹ 

         

        • Antibody (Trastuzumab) + Linker + Maytansinoid (Anticancer Agent)¹²

           

      • Mechanism of Action (Maytansine and Auristatins):

        • Maytansinoids are classified as microtubular polymerization inhibitors.

          • This agent is derivative of a naturally occurring benzoansamacrolide, maytansine, obtained from the bark of the African shrub Maytenus ovatus.¹¹

             

            • Maytenus ovatus

              Attribution: Vasanthakuman K Sumesh KS Shimelis T Maytenus ovatus An African Medicinal Plant Yielding Potential Anti-cancer Drugs. Biomedical J of Scientific & Technical Research 1 (7), 1-3, 2017. https://biomedres.us/pdfs/BJSTR.MS.ID.000571.pdf

      • Clinical Use and Toxicity (Maytansinoid-1):¹⁰

        • Maytansinoid-1 (DM1) is an example of an antibiotic drug conjugate (ADC) consisting of the antibody ado-trastuzumab emtansine (T-DM1), the thioether linker, and the maytansinoid anticancer drug.

          • This ADC was approved by the FDA for treating HER2 -positive metastatic breast cancer in those patients who had previously undergone trastuzumab and taxane treatment protocols.

            • From experience in a prominent clinical trial, this ADC was associated with side effects including:

              • Thrombocytopenia

              • Temporary transaminitis

              • Nausea

              • Myalgias

              • Fatigue and

              • Arthralgias.¹⁰

    • Aurastatins: Monomethyl auristatin E (MMAE)¹⁰

      • Monomethyl auristatin E (MMAE)

      • Monomethyl auristatin E (MMAE) is linked to a monoclonal antibody against CD30 (a.k.a.TNFRSF8) which is a cell membrane protein belonging to the tumor necrosis factor receptor family.^10,14  

        • CD30 is expressed by activated T and B cells.^14,15,16  

        • CD30 interacts with tumor necrosis factor 2 (TRAF2) and tumor necrosis factor 5 (TRAF5), resulting in activation of NF-κB.

          • TRAF2 (TNF Receptor-Associated Factor 2)¹⁷

        • NF-κB, a protein complex controlling DNA transcription, cytokine production and cell survival localized in nearly all animal cell types.^14,15,16  

      • Monomethyl auristatin E is an anti-mitotic agent which binds to the vinca alkaloid binding site, inhibiting tubulin polymerization.¹⁰ 

        • Compared to most cancer chemotherapeutic agents, auristatins and maytansinoids are a 100 to 1,000-fold more cytotoxic.

        • Monomethyl auristatin E is derived from peptides found in marine shell-less mollusk Dolabella auricularia.¹⁹ 

           

          • Dolabella auricularia²⁰

          • These peptides are known as dolastatins.

      • The monoclonal antibody associated with monomethyl auristatin E is brentuximab vendotin.¹⁰ 

        • Drug release is designed to occur in the lysosome/endosome compartment directed to that location by the linker, a peptide-based cathepsin-B substrate.

           

          • "Skeletal formula of a monomethyl auristatin E (MMAE) / monoclonal antibody (MAB) conjugate"¹⁸

            "Skeletal formula of a monomethyl auristatin E (MMAE) / monoclonal antibody (MAB) conjugate. "The spacer (para-aminobenzylcarbamate) is marked in green, the cathepsin-clevable linker (Val=valine, Cit=citruloline) is blue, and the attachment group (consisting of maleimide and caproid acid) is brown. "The whole radical inside the four boxes is called vedotin."

       

      • Clinical Use (Monomethyl auristatin E):

        • Clinical approval for anticancer use of monomethyl auristatin E has been obtained for refractory Hodgkin's lymphoma or anaplastic large cell lymphoma.¹⁰   

         

        • Brentuximab Vedotin Pharmacology (monomethyl auristatin E)²¹

          Attribution: Hamlin PA "Dr. Hamlin on Brentuximab Venotin Pharmacology. "https://www.youtube.com/watch?v=k0uTgGMZHYY (1/2012) OncLiveTV Youtube Channel:  https://www.youtube.com/channel/UC3aRpa3CR_w4JrxYv_r_pDg

         

      • Toxicities: (Monomethyl auristatin E):¹⁰

        • Common toxicities associated with monomethyl auristatin E administration include:

          • Peripheral neuropathy

          • Nausea
            Fatigue, each of which may occur in about 30%-40% of patients.

        • Dose-limiting toxicities have been identified and include:

          • Thrombocytopenia

          • Hyperglycemia

          • Diarrhea

          • Vomiting.

        • This agent is contraindicated for use with bleomycin as a result of increased pulmonary toxicity and  risk of a virus-induced progressive multifocal leucoencephalopathy.