2014年06月04日

Seminar 03-06-2014 (Tan)

Title: Antibody-drug conjugates: an emerging concept in cancer therapy
(Ravi V. J. Chari et al. Angew Chem. Int. Ed. 53 (2014) 3796–3827)


Running title: Antimitotic agents (Maytansinoids) as ADC Payloads

D2 TAN

Introduction
Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach because their selectively binding to cancer cells. However, too limited monoclonal antibodies were explored with sufficiently potent. On the other hand, so many nature products isolated with extremely high potency on killing cancer cell, however, after clinical studies, the activity became insufficient due to the lack of therapeutic activity (toxicity to normal cells).
Antibody–drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first-generation ADCs have led to improvements in every aspect of this technology, i.e. , the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed.

a) What is antibody–drug conjugate (ADC): ADCs link cytotoxic agents to monoclonal antibodies that bind to tumor cell-specific antigens or to antigens that are overexpressed on the surface of tumor cells. ADCs are made up of three parts: a monoclonal antibody, a cytotoxic drug, and a linker that joins the two together.
Key Requirements: 1. The cytotoxic drug: For an ADC to be therapeutically active, the cytotoxicity should has activity with picomolar range, good aqueous stability and reasonable aqueous solubility. 2. The linker: Initially, the drugs mixed with the antibody in aqueous solution in the presence of the coupling agent EDC (N- ethyl-N’-(3-dimethylaminopropyl) carbodiimide hydrochlo- ride) to enable amide bond formation with amino groups of the antibody. Later, disulfide-based linkers (selectively broken down inside the tumor cell where the concentration of thiols is higher than in the blood) and peptide linkers (broken down by enzymes found inside the tumor cell) were developed. 3. The antibody: The binding site should be on the surface, the efficiency of internalization process is an important factor to consider in the selection of an antigen target for ADCs.
b) Primary mechanism of action: After binding the target antigen, the ADC-antigen complex is typically internalized and transported to intracellular organelles where release of the attached drug can occur. Upon release, the cytotoxic drug can interfere with various cellular mechanisms, leading to cell death. (Fig.1)
1

Figure 1: Primary Mechanism of Action of Antibody-Drug Conjugates
c) Maytansinoids as ADC Payloads (AMC): Maytansine (1) is a benzoansamacrolide that was first isolated from the bark of the Ethiopian shrub Maytenus ovatus in 1972. (Fig.2) Maytansine bind to tubulin near the Vinca alkaloid binding site, and are thought to have a high affinity for tubulin located at the ends of microtubules. Maytansine was extensively evaluated in human clinical trials, but failed to demonstrate a therapeutic benefit at tolerable doses. However, the unusually high cytotoxic activity of the maytansinoids makes them attractive candidates for antibody-targeted delivery. In addition, maytansine met other key criteria, such as good aqueous stability and reasonable aqueous solubility, for use as a payload for ADCs. Maytansine, however, does not possess an obvious functional group that can be used to link it to an antibody.
2

Figure 2: Chemical structure of Maytansinoids (1)
d) Prepareation of AMCs: Maytansinoids was conjugated with antibody by disulfide linker (SPDB) and thioether linkers (MCC).
3

Fig.3 Conjugation of maytansinoids to antibody by disulfide linker and thioether linkers
e) In vitro cytotoxicity of AMCs: The AMCs with the disulfide linkers were able to kill the antigen-negative cells (also known as bystander cells) as long as enough antigen-positive cells were present. The AMCs with hindrance on the maytansinoid side of the disulfide bond were found to have similar degrees of bystander killing. The AMC with the noncleavable thioether linker, however, had no bystander killing, as it could not kill antigen-negative cells, even when large amounts of antigen-positive cells were added.
f) Cellular catabolism of AMCs: All conjugates gave lysine-bearing catabolites that had an intact linkage with the unaltered maytansinoids. The conjugate with a noncleavable thioether linker gave lysine-linker-maytansinoid as the sole catabolite, while the conjugates with disulfide linkers produced additional catabolites. The proposed mechanism for the metabolism of each conjugate is shown Fig.4. In the case of AMCs with the noncleavable linker, the sole lysine-linker-maytansinoid catabolite produced can bind to tubulin in the cytoplasm to disrupt microtubule dynamics and induce cell killing, or it can be effluxed from the cell. For AMCs with disulfide linkers, some of the initially generated lysine-bearing catabolite is cleaved by reduction in the cytoplasm to release the thiol-containing maytansinoids DM1 or DM4, which can be further S-methylated by an endogenous S-methyl transferase enzyme. Since these metabolites are uncharged, they are able to efflux out of the cell and diffuse into bystander cells to kill them.
4

Figure 4: Proposed mechanism for AMCs catabolism and potential bystander cell killing.
g) Tolerability and efficacy of AMCs: The circulation half-life of AMCs with disulfide linkers was dependent on the degree of steric hindrance of the disulfide linkage; as hindrance was increased, the clearance rate was progressively decreased. In a majority of cases an AMC with the optimal disulfide linker is more active in vivo than the corresponding conjugate with a noncleavable linker.
h) In vivo catabolism of AMCs: Both AMCs were efficiently detoxifies by mouse liver through oxidation.

Outlook: The concept of target delivery of drugs improves the selectivity and reduces the side toxicity could be applied in wide field of research. For example, last seminar I reported bisphosphonates as anti-osteoporosis agent, however, with strong side effect, like inflammatory, gastrointestinal disorders and so on. If we use antibody conjugate as a target delivery, for example target to RANKL, and cleave the linker between bisphosphonates and antibody, and release the free bisphosphonate selectively to bone cell. Another imagination, how could we delivery ursolic acid target to the bone but not cause any side effect of cytotoxicity of other cell. For example using the MAb specific target to the plasma membrane of osteoclast cell, through internalization process, ursolic acid would only release in the osteoclast. To apply these imaginations, linker design of conjugate in the key problem.


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