• Biomolecules & Therapeutics
• /
• v.23 no.6
• /
• pp.493-509
• /
• 2015

Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris$^{(R)}$(anti-CD30-drug conjugate) and Kadcyla$^{(R)}$(anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed.

• Bulletin of the Korean Chemical Society
• /
• v.25 no.10
• /
• pp.1449-1450
• /
• 2004

• Journal of Microbiology and Biotechnology
• /
• v.29 no.11
• /
• pp.1799-1805
• /
• 2019

Doxorubicin (DOX) is one of the most effective anticancer agents used for the treatment of multiple cancers; however, its use is limited by its short half-life and adverse drug reactions, especially cardiotoxicity. In this study, we found that the conjugate of DOX with APTA12 (Gemcitabine incorporated G-quadruplex aptamer) was significantly more cancer selective and cytotoxic than DOX. The conjugate had an affinity for nucleolin, with higher uptake and retention into the cancer cells than those of DOX. Further, it was localized to the nucleus, which is the target site of DOX. Owing to its mechanism of action, DOX has the ability to intercalate into the nucleotides thus making it a suitable drug to form a conjugate with cancer selective aptamers such as APTA12. The conjugation can lead to selectively accumulate in the cancer cells thus decreasing its potential nonspecific as well as cardiotoxic side effects. The aim of this study was to prepare a conjugate of DOX with APTA12 and assess the chemotherapeutic properties of the conjugate specific to cancer cells. The DOX-APTA12 conjugate was prepared by incubation and its cytotoxicity in MCF-10A (non-cancerous mammary cells) and MDA-MB-231 (breast cancer cells) was assessed. The results indicate that DOX-APTA12 conjugate is a potential option for chemotherapy especially for nucleolin expressing breast cancer with reduced doxorubicin associated side effects.

• Archives of Pharmacal Research
• /
• v.21 no.5
• /
• pp.595-598
• /
• 1998

The rate of the GSH conjugate formation, the inhibition of DNA topoisomerase-I and the cytotoxic activity against L1210 cells of the naphthoquinones showed the same order; 5,8-dimethoxy-1,4-naphthoquinone (DMNQ)>6-(1-hydroxyethyl)-DMNQ>2-(1-hydroxyethyl)-DMNQ; the steric hindrance of the substituents, particularly 2-substutuent, in reacting with cellular nucleophiles must be the main cause for lowering the bioactivities. Acetylation of 2-(1-hydroxyethyl)-DMNQ producing 2-(acetyloxyethyl)-DMNQ potentiated the bioactivities; 2-(-hydroxyethyl)-DMNQ did not react with GSH and the enzyme, and showed $ED_{50}$ of 0.146 mg/ml for the cytotoxcity. Furthermore, the acetylation 2-(1-hydroxyethyl)-DMNQ(T/C, 119%) enhanced the T/C values for the mice bearing S-180 tumor {T/C of 2-(1-acetyloxyethyl)-DMNQ, 276%]. It was assumed that the difference in bioactivities ensued by acetylation was based on the mechanism of the so-called bioreductive alkylation.

• Bulletin of the Korean Chemical Society
• /
• v.32 no.3
• /
• pp.873-879
• /
• 2011

5-Fluorouracil (5-FU), an anticancer agent was covalently attached to the recently developed sorbitol-based G8 transporter, and the conjugate (7) with FITC was found to have an affinity toward mitochondria and to readily cross BBB to gain an entry into mouse brain. Measured by $IC_{50}$, the conjugate (9) without the fluorophore showed enhanced cytotoxic activity toward two types of multidrug-resistant cell lines. These results strongly suggest that the sorbitol-based G8 transporter can be utilized as a good CNS delivery vector.

• Biomedical Science Letters
• /
• v.27 no.3
• /
• pp.121-133
• /
• 2021

Antibody-drug conjugates (ADCs) are drawing much interest due to its great potential to be one of the important options in cancer treatments. ADCs are acting like a magic bullet which delivers cytotoxic drugs specifically to cancerous cells throughout the body, thus attacks these cells, while not harming healthy cells. ADCs are complex molecules that are composed of an antibody having targeting capability and linked-payload or cytotoxic drug killing cancerous cells. The key factors of the success in the development of ADC are selection of appropriate antibody, cytotoxic payload and linker for conjugation. Recently there was considerable progress in ADCs development, and a large number of ADCs gained US FDA approval. About 80 new ADCs are under active clinical studies. In this review we present a brief introduction of the US-FDA approved ADCs and global situation in the clinical studies of ADC pipelines. We address an overview on each component of an ADC design such as target antigens, payloads, linkers, conjugation methods, drug antibody ratio. In addition, we discuss on the trend of ADC market where global big pharmas and domestic biopharmaceutical companies are competing to develop safer and more effective ADCs.

• Archives of Pharmacal Research
• /
• v.23 no.1
• /
• pp.22-25
• /
• 2000

Formation of glutathione (GSH) conjugates with 2- or 6-(1-hydroxymethyl)- and 2-(1-hydroxyethyl)-DMNQ derivatives (DMNQ, 5,8-dimethoxy-1,4-naphthoquone was carried out in phosphate buffer (pH 7.4), in the presence of glutathione-S-transferase (GST), in rat liver S-9 fraction and by perfusion, and the rates of conjugates formation were compared and correlated to cytotoxicity. The GSH conjugates of 6-(1-hydroxyalkyl)-DMNQ derivatives were formed faster than 2-(1-hydroxyalkyl)-DMNQ derivatives under all of the media, implying that steric hindrance was the cause of lowering the rate of conjugate formation of 2-substituted derivatives. For both isomers, addition of GST did not improve the reaction rate, compared with that in buffer, while the reaction in the S-9 fraction and the perfusate was accelerated to a great extent. The catalytic effect of the S-9 fraction and the perfusate contain an effective system relaxing the steric hindrance of 2-(1-hydroxyalkyl)-DMNQ derivatives. Furthermore, a good correlation between the formation of the GSH conjugates and the cytotoxic activity of both naphthazarin isomers suggests that the steric hindrance is a cause of lowering the cytotoxicity of 2-isomers.

• Journal of Radiopharmaceuticals and Molecular Probes
• /
• v.7 no.1
• /
• pp.33-40
• /
• 2021

Recently, antibody-drug conjugates (ADCs) are used to deliver efficient cytotoxic payloads selectively in cancer cells. In the designing of an ADC, the antibody is connected to a toxic payload via a covalent linker, which helps to solubilizes the typical hydrophobic payload as well as stabilizes the linkage over circulation. The development of the linkers for the antibody drug conjugate is still in demand. Initially, the acid, disulfide, and cathepsin-sensitive ADCs attracted considerable attention for the delivery of a potent cytotoxic payload but suffer from instability in human and mouse plasma with a short half-life. In addition, It also suffer from a solubility issue that induces aggregation, which is the major problem in their development. ADCs associated with sulfatase and phosphatase cleavable linker are highly soluble due to the anionic nature of sulfate and phosphate groups. The ADCs also showed high stability in human and mouse plasma. Therefore, to overcome these limitations, sulfatase and phosphatase cleavable linkers were developed. This review focuses on the recently reported advantages of sulfatase and phosphatase cleavable linkers for ADCs.

• BMB Reports
• /
• v.44 no.7
• /
• pp.423-434
• /
• 2011

A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review.

• Journal of Animal Science and Technology
• /
• v.47 no.1
• /
• pp.19-28
• /
• 2005

The objectives of the current study were to develop polyclonal antibodies in sheep against adipocyte plasma membrane(APM) proteins isolated from swine, to investigate tissue specificity, and to determine cytotoxic effects of antiserum on swine adipocytes. Plasma membrane proteins from adipocyte, brain, heart, kidney, liver, and spleen were isolated using a 32% sucrose gradient. Adult male sheep was immunized three times at three week interval with the purified swine APM proteins. Antiserum was taken from immunized sheep at 10, 12, and 14 days after the third immunization. Antiserum expressed strong reactivity with APM proteins determined by enzyme-linked immunosorbent assay(ELISA), and the reactivity could be detected at dilutions in excess of 1 : 81,000. Antiserum showed very low binding affinity with proteins isolated from brain, heart, kidney, liver, or spleen. Tissue specificity of the antiserum was reconfirmed by Western immunoblotting using anti-sheep immunoglobulin G•alkalinephosphatase conjugate as a secondary antibody. The reactivity of antiserum to the external surface of fixed swine adipocytes was confmned by an immunohistochemical technique using anti-sheep immunoglobulin G-FITC. Confluent swine adipocytes in culture were lysed by antiserum treatment and cytosolie lactate dehydrogenase(LDH) was released as a dose-dependent patterns while adipocytes treated with normal sheep serum maintained their integrity and expressed low level of LDH. These results implicate that fat contents in the pigs can be reduced by immunological methods.