ADEPT
Encyclopedia
ADEPT is a strategy to overcome the problems of lack of tumor
selectivity. An antibody designed/developed against a tumor antigen
is linked to an enzyme
and injected to the blood, resulting in selective binding of the enzyme in the tumor. When the discrimination between tumor and normal tissue enzyme levels is sufficient, a prodrug
is administrated into the blood circulation, which is converted to an active cytotoxic drug by the enzyme, only within the tumor. Selectivity is achieved by the tumor specificity of the antibody and by delaying prodrug administration until there is a large differential between tumor and normal tissue enzyme levels.
ADEPT has shown antitumor activity in animal tumor models of human choriocarcinoma
and colonic and breast carcinoma.
, London
, using an anti-CEA F(ab′)2 antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2).
The antibody used in the first ADEPT clinical trial was of murine origin and the enzyme was bacterial. Host antibodies to both components of the AEC were present in the blood of all non-immunosuppressed patients by day 10 after AEC infusion. Several patients received ciclosporin
since it had been shown in rabbits that this could delay the appearance of host antibodies to soluble proteins.
A subsequent, small-scale trial at the Royal Free Hospital
, London, used the same agents as in the Charing Cross Hospital trial but the protocol was modified to provide additional pharmacokinetic data and most patients received only a single course of treatment .
-directed enzyme prodrug therapy (GDEPT), virus-directed enzyme prodrug therapy (VDEPT), PDEPT (Polymer-Directed Enzyme Prodrug Therapy), LEAPT (Lectin-directed enzyme-activated prodrug therapy), and CDEPT
(Clostridial-directed enzyme prodrug therapy).
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
selectivity. An antibody designed/developed against a tumor antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
is linked to an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
and injected to the blood, resulting in selective binding of the enzyme in the tumor. When the discrimination between tumor and normal tissue enzyme levels is sufficient, a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
is administrated into the blood circulation, which is converted to an active cytotoxic drug by the enzyme, only within the tumor. Selectivity is achieved by the tumor specificity of the antibody and by delaying prodrug administration until there is a large differential between tumor and normal tissue enzyme levels.
ADEPT has shown antitumor activity in animal tumor models of human choriocarcinoma
Choriocarcinoma
Choriocarcinoma is a malignant, trophoblastic and aggressive cancer, usually of the placenta. It is characterized by early hematogenous spread to the lungs...
and colonic and breast carcinoma.
ADEPT history
The first pilot-scale clinical trial of ADEPT was carried out at Charing Cross HospitalCharing Cross Hospital
Charing Cross Hospital is a general, acute hospital located in London, United Kingdom and established in 1818. It is located several miles to the west of the city centre in the London Borough of Hammersmith and Fulham....
, London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...
, using an anti-CEA F(ab′)2 antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2).
The antibody used in the first ADEPT clinical trial was of murine origin and the enzyme was bacterial. Host antibodies to both components of the AEC were present in the blood of all non-immunosuppressed patients by day 10 after AEC infusion. Several patients received ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
since it had been shown in rabbits that this could delay the appearance of host antibodies to soluble proteins.
A subsequent, small-scale trial at the Royal Free Hospital
Royal Free Hospital
The Royal Free Hospital is a major teaching hospital in Hampstead, London, England and part of the Royal Free Hampstead NHS Trust....
, London, used the same agents as in the Charing Cross Hospital trial but the protocol was modified to provide additional pharmacokinetic data and most patients received only a single course of treatment .
Other versions of directed enzyme prodrug therapy (DEPT)
There are several other strategies to use prodrug/enzyme systems for cancer therapy, including geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
-directed enzyme prodrug therapy (GDEPT), virus-directed enzyme prodrug therapy (VDEPT), PDEPT (Polymer-Directed Enzyme Prodrug Therapy), LEAPT (Lectin-directed enzyme-activated prodrug therapy), and CDEPT
CDEPT
Clostridial-directed enzyme prodrug therapy is the use of Clostridia to convert prodrugs into active drug agents. It is comparable to a more popular strategy, called ADEPT.- The CDEPT strategy :...
(Clostridial-directed enzyme prodrug therapy).