Antibody Directed Enzyme Prodrug therapy is a technique of active drug targeting therapy which was developed to reduce cancer chemotherapy associated Toxicity

1. ADEPT
Antibody Directed Enzyme Prodrug
Therapy
Presentation By
Mohammad Adeel Zafar
PhD Research Scholar
Centre for Biomedical Engineering
Indian institute of Technology (IIT) Ropar
Rupnagar, Punjab, 140001

2. FLOW OF PRESENTATION
• Introduction
• Cancer therapy
• Challenges in cancer Therapy
• Adept
• Chemistry
• Advantage
• Disadvantages
• Clinical trials

3. INTRODUCTION
• A drug is a chemical entity which is used in the diagnosis, cure, relief treatment or prevention of Disease.
• The drug when delivered In body is intended to affect the structure or function of the body
(Pharmacodynamics)
• Apart from desired pharmacodynamic effect the drug sometimes shows different adverse effects which
are undesired and harmful
• The process of delivering drug at target site after crossing different barrier created by our body , is
known as Pharmacokinetics
• In the process of drug delivery there are still a lot of problems which need to be addressed
• One of the approach is prodrug therapy

4. CANCER THERAPY
• Depending upon type of cancer, cancer therapy can be surgery, chemotherapy and/or
radiotherapy
• There are some other approaches like Targeted therapies, Immuno therapy, Hormone
therapy, Stem cell transplant and Precision medicine which are available for some
cancer types
• A cancer patient might receive many different types of therapy, including those aimed at
relieving the symptoms of cancer, such as pain.

5. CHALLENGES IN CANCER THERAPY
• Cancer is clearly the most deadly disease in the developed world as one in three people develop cancer during
their lifetime
• The cure for cancer is like the Holy Grail since most of the existing treatments are not effective enough to provide
full protection from this disease
• Reason for difficulties in cancer treatment May be :
o Targeting cancer stem cells (CSCs) is difficult
o Drug resistance properties of cancer stem cells make them immune to anticancer drugs
o Lack of cancer epigenetic profiling and specificity of existing epi-drugs
o Problems associated with cancer diagnosis make it difficult to treat
o Unavailability of effective biomarkers for cancer diagnosis and prognosis
o Limitations of conventional chemotherapeutic agents
o Metastasis poses a huge problem in cancer treatment
Chakraborty, et al (2012).

6. ANTIBODY DIRECTED ENZYME PRODRUG THERAPY
(ADEPT)
• ADEPT is basically a two step targeted drug delivery mechanism which wa designed to localize more active
drug at tumor site and very less at normal tissue
• In first step Antibody-prodrug activating Enzyme conjugate (AEC) is targeted to the tumor through
intravenous administration
• In second step a non-toxic Prodrug is injected systemically that is converted to its corresponding active
form by the enzyme
*Optimization of the interval between both thre step is crucial to guarantee an accumulation of the AEC at target site
rather than normal tissue to decrease the toxicity

8. CHEMISTRY
• Ab-Enzyme conjugate (AEC) can be made by using
• Hetro-Bifunctional reagent
• Recombinant Technology
• Genetic Engineering (To humanize rodent monoclonal antibody)
* By retaining only antigen binding site of original non-human antibody the
immunogenicity can be reduced
*Hypermanosylation of fusion protein can increase clearance rate

9. ENZYME-PRODRUG
Enzyme Drugs Remark
Alkaline Phosphatase Etoposide, Mitomycin, Phenol
Mustard
Negative side effect by
endogenous enzymes is observed
Amino - Peptidase Melphan
Carboxy Peptidase G2 (CPG2) Nitrogen mustard For self immolative drugs
Beta - Lactamase Nitrogen mustard, Doxorubicin,
Vinblastine, Taxol, Carboplatin
Most widely studied

10. ADVANTAGES
• Bystander effect – Good lipophilicity of active drug can allow penetration to even
those tumor cell which doesn’t express the antigen.
• Amplification effect – One enzyme molecule can activate many prodrug
molecule
• Easy tumor penetration due to small size of system
• Separate administration provides sufficient time for the process
• Decrease risk of 2nd therapy induced cancer due to localization at tumor site
• Extremely potent anticancer agents can be administered without a fear of killing
normal cell

11. DISADVANTAGES/ CHALLANGES
• AEC might have
o Poor tumor penetration
o in-vivo dis-integration
o presence of Blood antigen decreases availability at tumor site
o Chances of Immunogenicity with non-human enzyme and lack of specificity with
human enzyme
o Inadequate clearance of unbound AEC
o High Cost

12. CLINICAL TRIALS
Clinical trial 1 :
• In 1991 Very first clinical study of ADEPT utilized CPG2 (bacterial enzyme) conjugated to F(ab)2
fragment of A5B7 ab (a murine anti-CEA monoclonal ab) for activating CMDA (Benzoic acid
mustard prodrug)
• A second glycosylated SB43 ab directed to CPG2 active site was used as enzyme inhibitor and
clearing agent for AEC
• A5B7-F(ab)2 – CPGA + SB43(gal) + CMDA
Clinical trial 2 :
• In 1993 same combination was used but with half of the dose due to side effect
(myelosuppression) of original dose

13. Clinical trial 3 :
A5B7-F(ab)2 – CPG2 + BIP Prodrug (ZD2767P)
Clinical trial 4 :
MFECP Fusion protein + BIP Prodrug (single cycle & multiple cycle)
*MFECP is a high affinity anti-CEA single chain Fv antibody fragment fused to CPG2