ADEPT (Antibody Directed Enzyme Prodrug Therapy: Its recent advances

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This presentation includes details about ADEPT(Antibody Directed Enzyme prodrug Therapy), various challenges that one should meet to design an ADEPT and various enzymes and prodrugs that are reported and also the data of clinical studies.

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ADEPT (Antibody Directed Enzyme Prodrug Therapy: Its recent advances

  1. 1. GE-511 PRESENTED BY GANDRATHI KULDEEP KUMAR M.S.(PHARM), I SEMESTER DEPARTMENT OF PHARMACEUTICS NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH 1
  2. 2. Introduction Antibody-Directed Enzyme-Prodrug Therapy Advances in ADEPT Conclusion 2
  3. 3.  Many therapies are used for the treatment of cancer  These therapies suffer from many limitations  Limitation to the on-going treatments is due to  Drug resistance  Lack of selectivity  Pathway redundancy  Many chemotherapeutic agents-narrow therapeutic index  A more efficient approach is needed 3
  4. 4.  It was proposed by Dr. Bagshawe et al  Advantageous over conventional therapies  Involves 2 steps:  Administration and localization of antibody-enzyme complex in tumor cell  Selective conversion of prodrug by antibody-enzyme fusion protein 4 Afshar, S et al., Molecular cancer therapeutics 8, 185.
  5. 5. TUMOR CELL Mechanism of ADEPT 5
  6. 6. 6 Bagshawe, K.D et al., 1999. Current opinion in immunology 11, 579-583.
  7. 7.  Better understanding of the therapy  Identification of antigen  Penetration of antibody-enzyme fusion protein  Elimination of biological molecules might be non-linear  Enzyme specific prodrug activation 7 Fang et al., 2008. Drug Metabolism and Disposition 36, 1153-1165.
  8. 8. Use of different enzymes in ADEPT Modifications in antibody-enzyme complexes Phase-I clinical studies Optimization of ADEPT- mathematical models ADVANCEMENTS IN ADEPT 8
  9. 9. 9 Enzymes employed in ADEPT Non-human enzymes Intracellular human enzymes Engineered human enzymes
  10. 10. 10  Vast number of prodrugs can be designed  Bacterial enzymes are generally employed  Many studies were reported on bacterial carboxypeptidase G2  Limited by their immunogenecity  Modified, in the recent times, to reduce immunogenecity Example: Reduction in immunogenecity of β-lactamase
  11. 11. 11 Contd...  Non-human enzymes are more efficient compared to human enzymes Example: Activation of prodrug CPT-11 to the active drug SN-38 is very fast using rabbit carboxylesterases compared to the human enzymes
  12. 12. 12  These are produced by inducing mutations in human enzymes  Less immunogenic compared to non human enzymes  Substrate specificity of wild type enzymes is altered Example: Double mutant (hDM) of human Poly Nucleoside Phosphorylase (hPNP) Afshar, S et al., Molecular cancer therapeutics 8, 185.
  13. 13. 13  They are present only within the cell  No systemic activation of prodrugs will be observed  Recent strategy employed in ADEPT  Less immunogenic compared to non human enzymes and engineered human enzymes Example: Post Proline cleaving endopeptidase N-Protected glycine- proline dipeptide doxorubicin Doxorubicin Heinis, C et al., 2004. Biochemistry 43, 6293-6303.
  14. 14. S.No Enzyme Prodrug Drug 1 DT diaphorase 5-(Aziridin-1-yl)-2,4- nitrobenzamide (CB 1954) 5-(Aziridin-1-yl)-4- hydroxyl amino-2- nitrobenzamide. 2 Plasmin Peptidyl-p-phenylene diamine- mustard Phenylenediamine- mustard 3 Carboxypeptidase G2 Benzoic acid mustard glutamates Benzoic acid mustards (various) 4 Thymidine kinase (viral) Ganciclovir* Ganciclovir triphosphate 5 Cytosine deaminase 5-Fluorocytosine* 5-Fluorouracil 6 β –Glucosidase Amygdalin Cyanide 7 β –Lactamase Nitrogen-mustard- cephalosporin Nitrogen mustards (various) 8 Alkaline phosphatase Phenol mustard phosphatase* Doxorubicin phosphatase* Phenol mustard Doxorubicin 9 Cytochrome P-450 Cyclophosphamide Ifosfamide Phosphoamide mustard (+ acrolein) 14 Enzymes and prodrugs proposed for cancer therapy
  15. 15. 15  Use of humanized antibodies and enzymes Example: humanized disulfide-stabilized anti p185HER2 Fv-β-lactamase fusion protein  Accelerated clearance of Ab-E fusion protein  Usage of clearance antibody  Hypermannosylation of recombinant antibody- enzyme fusion protein Rodrigues et al., 1995. Cancer Res 55, 63-70.
  16. 16. 16  Produced via post translational modifications in Pichia pastoris  Elimination is well understood  Complex eliminates via mannose receptors  Macrophages (spleen) and endothelial cells (liver) are mainly responsible for the elimination of complex
  17. 17. 17  With A5CP conjugate and CMDA prodrug  It required additional clearance antibody  100% patients developed HAMA and 97% HACA  With recombinant MFECP1 and Bis-iodo phenol prodrug  Only 31 patients were taken  36% patients developed HACA and none of them developed HAMA
  18. 18. 18 Treatment with MFECP1 (units/m2) and BIP prodrug (mg/m2 X3) No. of patients Toxicity 5000 MFECP1 + 12.42 BIP prodrug Plasma CPG2 0.0111units/mL (median) 3 G3 thrombocytopenia (1), G3 neutropenia (1), G3 leukopenia (1) 5000 MFECP1 + 1075 BIP prodrug Plasma CPG2 <0.002units/mL 1 G4 ALT/AST, G3 GGT, G4 Cr/urea, G3 anemia, G3 leukopenia, G3 thrombocytopenia 3000 MFECP1 + 537.6 BIP prodrug Plasma CPG2 <0.002units/mL 2 G4 ALT/AST (1), G3 anemia (1), G3 thrombocytopenia (1), G3 leukopenia (1), G3 fatigue 1500 MFECP1 +200 BIP prodrug 1 G3 thrombocytopenia (1) Abbrevations: G3 :Grade 3, G4: Grade 4, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase GGT: ϒ-glutamyl transferase Dose escalation and toxicity of BIP prodrug Mayer, A. et al., 2006. Clinical cancer research 12, 6509-6516.
  19. 19. 19  To predict therapeutic outcome before preclinical and clinical studies  Two models were applied:  Compartmental model: Failed to describe pharmacokinetic properties of biological molecules  Physiology based Pharmacokinetic (PBPK) model: Applied to analyse each compartment or organ. Galluppi et al., 2001. Clinical pharmacology and therapeutics 69, 387.
  20. 20. 20 For an effective ADEPT  Optimal clearance of Ab-E is 1.5X10-3 ml/min  Optimal Emax of Ab-E for prodrug conversion is 600 min-1  Optimal Permeability of prodrug is 1.4 X 10-4 cm/sec  Optimal dosing interval of Ab-E and prodrug is 5 days Galluppi et al., 2001. Clinical pharmacology and therapeutics 69, 387.
  21. 21. 21  ADEPT was proved to be a potential therapy for the treatment of cancer. Clinical trials of ADEPT proved this fact but the therapy is limited by toxic effects, many of which were being addressed in the recent years  Further research has to be encouraged in the future as ADEPT has the potential of being the successful therapy in the treatment of cancer in the future
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