DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies (original) (raw)
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Molecular cancer therapeutics, 2018
Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similarpotency, but improved bystander killing andefficacy, compared with those of the cross-linker. Thus, the improvedtolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.
A New Class of Antibody-Drug Conjugates with Potent DNA Alkylating Activity
Molecular cancer therapeutics, 2016
The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here we describe the development of a new class of potent DNA alkylating agents that meets these objectives. Through chemical design, we changed the mechanism of action of our novel DNA crosslinking agent to a mono-functional DNA alkylator. This modification, coupled with linker optimization, generated ADCs that were well tolerated in mice and demonstrated robust antitumor activity in multiple tumor models at doses 1.5 - 3.5% of maximally tolerated levels. These properties underscore the considerable potential of these purpose-created, unique DNA-in...
Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications
Pharmaceuticals (Basel, Switzerland), 2018
Chemotherapy is one of the major therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an antibody, a cytotoxic payload, and a linker, which can offer selectivity against tumors, anti-cancer activity, and stability in systemic circulation. Therefore, we have reviewed recent updates and principal considerations behind ADC designs, which are not only based on the identification of tar...
ACS Medicinal Chemistry Letters, 2021
A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-pyrrol-3-yl)benzene ("MPB") payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the "MPB" binding component and guided structure−activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody−drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.
Bioconjugate Chemistry, 2019
Antibody−drug conjugates have elicited great interest recently as targeted chemotherapies for cancer. Recent preclinical and clinical data have continued to raise questions about optimizing the design of these complex therapeutics. Biochemical methods for site-specific antibody conjugation have been a design feature of recent clinical ADCs, and preclinical reports suggest that site-specifically conjugated ADCs generically offer improved therapeutic indices (i.e., the fold difference between efficacious and maximum tolerated doses). Here we present the results of a systematic preclinical comparison of ADCs embodying the DNA-alkylating linker-payload DGN549 generated with both heterogeneous lysine-directed and site-specific cysteine-directed conjugation chemistries. Importantly, the catabolites generated by each ADC are the same regardless of the conjugation format. In two different model systems evaluated, the site-specific ADC showed a therapeutic index benefit. However, the therapeutic index benefit is different in each case: both show evidence of improved tolerability, though with different magnitudes, and in one case significant efficacy improvement is also observed. These results support our contention that conjugation chemistry of ADCs is best evaluated in the context of a particular antibody, target, and linker-payload, and ideally across multiple disease models.
Antibody-Drug Conjugates: The New Frontier of Chemotherapy
International Journal of Molecular Sciences
In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents to be used as one of the tools in personalized cancer medicine. ADCs are comprised of a drug with cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. By providing a selective targeting mechanism for cytotoxic drugs, ADCs improve the therapeutic index in clinical practice. In this review, the chemistry of ADC linker conjugation together with strategies adopted to improve antibody tolerability (by reducing antigenicity) are examined, with particular attention to ADCs approved by the regulatory agencies (the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) for treating cancer patients. Recent developments in engineering Immunoglobulin (Ig) genes and antibody humanization have greatly reduced some of the problems of the first generation of ADCs, beset by problems, such as random co...
Drug metabolism and disposition: the biological fate of chemicals, 2016
Pyrrolobenzodiazepine-dimer (PBD-dimer) is a DNA minor groove alkylator and its CD22 THIOMAB antibody drug conjugate (ADC) through a disulfide linker demonstrated an efficacy of tumor reduction for more than 7-week with minimal body weight loss in xenograft mice after a single 0.5-1 mg/kg intravenous dose. The DNA alkylation was investigated here in tumors and healthy organs of mice to understand the sustained efficacy and tolerability. The experimental procedures included collection of tumors and organ tissues of xenograft mice treated with the ADC followed by DNA isolation/hydrolysis/quantitation and payload recovery from reversible DNA alkylation. PBD-dimer formed a considerable amount of adducts with tissue DNA, representing approximately 98% (24 h), and 99% (96 h) of the total PBD-dimer in tumors and 78-89% in liver and lung tissues, suggesting highly efficient covalent-binding of the released PBD-dimer to tissue DNA. The amounts of PBD-DNA adducts in tumor tissues were approxi...
THE NEW AGE SAVIOUR FOR COMBATING CANCER: ANTIBODY DRUG CONJUGATES.
Traditional techniques opted to treat cancer were found to be extremely harmful to the tissues when given at a slightly higher dose. ADCs (Antibody Drug Conjugates) have transformed the field of cancer chemotherapy. ADCs use monoclonal antibodies (mAbs) to explicitly tie tumour-related target antigens and convey an exceptionally powerful cytotoxic agent. The synergistic mix of mAbs conjugated too little molecule chemotherapeutics, through a stable linker, has given rise to an adequate class of anti-cancer drugs with an effectively extensive and quickly developing clinical pipeline. Antibody drug conjugates (ADCs) are an important division of therapeutics that allows the antigen-selective ability of mAbs to deliver highly potent cytotoxic drugs at the site of antigen-expressing tumor cells. The utilization of mAb coordinated delivery can present a high therapeutic index to exceptionally strong cytotoxic drugs, expanding both the efficacy and level of safety of the treatment. In other words, to achieve the goal of highly improved therapeutic efficacy and reduced toxicity, each component of an ADC i.e. the mAb, linker and the drug needs to be considered in context of targeted antigen. Furthermore, the mechanism of ADCs, characteristics of targets, methods of preparation, linker drugs being used in ADC design and regulatory requirements for new drug approval are discussed.
Advances in antibody-drug conjugates: A new era of targeted cancer therapy
Drug discovery today, 2017
Antibody-drug conjugates (ADCs), a potent class of anticancer therapeutics, comprise a high-affinity antibody (Ab) and cytotoxic payload coupled via a suitable linker for selective tumor cell killing. In the initial phase of their development, two ADCs, Mylotarg(®), and Adcetris(®) were approved by the US Food and Drug Administration (FDA) for treating hematological cancer, but the real breakthrough came with the discovery of the breast cancer-targeting ADC, Kadcyla(®). With advances in bioengineering, linker chemistry, and potent cytotoxic payload, ADC technology has become a more powerful tool for targeted cancer therapy. In addition, ADCs with improved safety using humanized Abs with a unified 'drug:antibody ratio' (DAR) have been achieved. Concomitantly, there has been a significant increase in the number of clinical trials with anticancer ADCs with high translation potential.