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  • br Conclusions Enzyme can be delivered

    2020-07-02


    Conclusions Enzyme can be delivered to the tumour by using humanised or fully human Cy3.5 maleimide receptor or even loaded into synthetic nanospheres produced from silica [64] or liposomally entrapped [65]. For any future ADEPT developments, a number of basic points need to be considered. As immunogenicity has been a major limitation of the CPG2 system, any new ADEPT would need to address this challenge. Other points to consider are that the target antigen should be expressed by the tumour cells only and if present on normal tissues, it should not be accessible to the circulating antibody-enzyme construct as in the case of CEA. The prodrug should be stable, water soluble and non-toxic so that it can be administered in larger doses by infusion. The drug should be highly toxic and with short half-life to avoid leak back from tumours. In addition, lesions created by the drug should not be repaired by the tumour cell. In the case of drug generated from CMDA, DNA damage/repair studies were not carried out but with the BIP drug, it has been shown that although DNA is cross-linked within minutes, the tumour is able to repair these cross-links within 24h [47]. Thus multiple cycles of therapy are necessary to sustain damage. Also, the prodrug to drug differential needs to be very high. Whereas the differential of the prodrug/drug pairs for CPG2 was about 100:1, Tietze et al. have reported a series of glycosidic prodrugs that are up to million times less toxic than the drug that showed IC50 of 110fM [13]. In addition, they have reported a glucuronide prodrug that was 1000–5000 fold less toxic than the parent duocarmycin drug [66]. These are most encouraging studies and should be developed for clinical investigations.
    Conflicts of interest Funding for ADEPT research over the years included Cancer Research UK, Post Natal Choriocarcinoma Trust, Royal Free Cancer Research Trust, AstraZeneca and National Translational Cancer Research Network.
    A major limitation of the use of cancer chemotherapy results from the lack of tumour specificity shown by most anticancer drugs. Many clinically used agents act predominantly through an antiproliferative mechanism which leads to damage of normally multiplying cells such as those of the bone marrow and gut. Therefore, chemotherapy is often linked to severe side effects due to the destruction of healthy tissue. One strategy to overcome this problem involves the use of non-biologically active prodrug derivatives of cytotoxic agents that can be selectively activated at the tumour site. In the antibody directed prodrug therapy (ADEPT) approach, an antibody–enzyme conjugate is used to localize an enzyme at the tumour site. A prodrug form of a cytotoxic agent, Cy3.5 maleimide receptor that can be converted to the active agent by the antibody-linked enzyme, is then administered systemically leading to selective release of the cytotoxic agent at the tumour site. An important feature of this system is that the releasing enzyme is of non-human origin (e.g., bacterial), thus avoiding release of the cytotoxic agent at other sites in the body. It has also been suggested that a bystander effect may enhance the efficacy of treatment, with the cytotoxic agent produced within the tumour diffusing out to neighbouring cells. One such system is presently in clinical trials and involves a fusion protein conjugate of the A5B7 F(ab’)(2) antibody and the enzyme carboxypeptidase G2 (CPG2) targeted against colorectal carcinoma expressing carcinoembryonic antigen (CEA). This is being used in conjunction with a nitrogen mustard prodrug ZD2767P (, ). However, with this combination of agents, therapeutic efficacy may be limited due to rapid repair of the DNA adducts formed after release of the cytotoxic agent, a commonly occurring phenomenon with mustard-based drugs. To address this issue, we have designed and synthesized two novel families of pyrrolobenzodiazepine (PBD)-based prodrugs (, and ,; ) that are not only more potent (i.e., picomolar) compared to mustard-based prodrugs but their adducts may be more resistant to repair,, thus reducing the probability of clinical resistance developing.