Inquiry Basket
BOC Sciences is a leading supplier of Antibody-Drug Conjugates (ADCs) products. We offer a wide range of ADC products including Disitamab vedotin, Teisotuzumab vedotin, Polatuzumab vedotin, Tisotumab vedotin, and others. Our ADCs are manufactured using state-of-the-art technology and are of the highest quality and purity. They are available in different formulations, including lyophilized powders, liquids and ready-to-use solutions. Our ADC supply capabilities are flexible and can be customized to meet customers' specific needs and are available in a range of packaging options, including bulk, vials and pre-fill.
As a new type of biological agents, ADCs have great potential in tumor treatment. ADCs deliver cytotoxic payloads directly to the desired site of action to enhance efficacy and minimize off-target effects. Antibody engineering technology can make ADC more uniform and stable, and a new generation of ADC drugs is in clinical trials, which is expected to improve the therapeutic effect and safety. In addition, with the research on more tumor-specific antigen targets and the in-depth understanding of the tumor cytotoxic drug release mechanism, ADCs are showing an explosive development trend in the field of tumor treatment. However, ADC also faces some challenges and constraints in application. The payload may escape or spread outside the cell, causing systemic toxicity and thus affecting therapeutic efficacy and safety. In addition, the process of antibody stability and large-scale production is complex and the preparation cost is high, which also limits its clinical promotion and application. Currently, there are at least dozens of ADC drug candidates undergoing clinical evaluation around the world.
Payload is a key component for ADC to exert its cytotoxic effect and must meet several main requirements: (1) High degree of cytotoxicity, usually with an IC50 value of low nanomolar or picomolar levels (Fig. 1); (2) Clear target and mechanism of action; (3) (potential) chemical attachment site. Maytansine derivatives (DM1/DM4) or Auristatin (MMAE/MMAF) are commonly used microtubule inhibitors. Other types of cytotoxic drugs include enediyne (carleomycin), doxycycline derivatives, pyrrolobenzodiazepine (PBD) and indolobenzodiazepine, all of which target small grooves of DNA. In addition, there are quinoline alkaloids (SN-38), which can inhibit DNA topoisomerase I. There is a lack of diversity in the ADC payloads used in clinical trials, with only 7 payload formulations reported. Six of the seven payload mixtures were derived from natural product sources, demonstrating the critical value of natural products in ADC payload types.
Fig. 1. Concentration ranges of commonly used ADC payloads.
One of the biggest challenges in ADC development is selecting the appropriate linker to conjugate the cytotoxic payload to the antibody. Linker chemistry affects various properties of the ADC, including toxicity, specificity, stability, and potency. Linkers can be broadly classified as cleavable linker (the payload can dissociate from the mAb at the tumor site) or non-cleavable linker (the payload remains bound to the mAb). Common cleavable linkers include chemically active linkers, acid-cleavable linkers, reducible chain linkers and enzyme-cleavable linkers. Non-cleavable linkers release cytotoxic payloads during lysosomal degradation of antibody-drug conjugates in the tumor environment, bypassing nonspecific dispersion of toxic agents. One advantage of non-cleavable linkers is improved stability in plasma and reduced off-target toxicity. Commonly used linker technologies and release mechanisms of ADC are shown in Table 1.
| Types of Linkers | Release Mechanism |
| Disulfide linkers | Designed to be cleaved via disulfide exchange with intracellular thiols such as glutathione |
| Hydrazone linkers | Designed for serum stability and degradation in the intracytoplasmic acidic compartment |
| Peptide linkers | Designed to be hydrolyzed by lysosomal proteases such as cathepsin B |
| Enzyme-cleavable linker | Designed to be cleaved by in vivo enzymes such as phosphatase, β-glucuronidases, β-galactosidase and sulfatases |
Table 1. Commonly used cleavable ADC linkers and mechanisms.
Drug-to-antibody ratio (DAR) refers to the average number of payload molecules conjugated to each antibody. This parameter is an important quality attribute directly related to the efficacy and safety of ADC. A low DAR can lead to reduced potency of the ADC, while a high DAR may alter the pharmacokinetics and toxicity profile of the ADC molecule. During the coupling process, changes in reactant concentration may lead to DAR differences, especially for randomly coupled ADCs. Therefore, coupling reaction control is the most critical step in process development. During production or post-production processing/handling, reasonable controls must be implemented to prevent the occurrence of unconjugated antibodies (naked anti-mAb) or low/high DAR heterogeneous entities to ensure that the expected DAR target value can always be achieved. Currently, representative DAR determination methods include hydrophobic interaction chromatography (HIC), reversed-phase liquid chromatography (RPLC), liquid mass spectrometry (LC-MS), ultraviolet-visible (UV/Vis) spectroscopy, and capillary electrophoresis-sodium dodecyl sulfate (CE-SDS).
The design of a clinically successful ADC depends not only on factors such as the potency of the payload and its ratio, linker stability, and release of the payload, but also on the choice of conjugation technology. All ADCs approved by the FDA over the past dozen years have been mixed with different amounts of drugs attached to different positions on monoclonal antibodies. The industry has developed a series of new conjugation strategies designed to control the link position and number of payloads while maintaining structural integrity and homogeneity. At present, ADC drug conjugation technology is generally divided into random conjugation and site-specific conjugation. Common methods of non-site-specific conjugation are Lys residue conjugation and Cys residue conjugation. Site-specific conjugation includes the introduction of reactive cysteine, disulfide bridges, non-natural amino acid conjugation, enzyme catalysis conjugation, glycosyl conjugation technology and proximity-induced antibody conjugation (pClick) technology.
Fig. 2. Random and site-specific conjugation strategy of ADC (Drug Discovery Today. 2014, 19(7): 869-881).
More than any other active pharmaceutical ingredient (API) class, the quality of ADC drugs is governed by the manufacturing process. In order to reproducibly produce a uniform subset of compounds, a sound manufacturing process is essential. In order to ensure process consistency, numerous parameters of the coupling process need to be studied and controlled. The selection of appropriate processing, storage and handling conditions during production should be based on physicochemical stability study data of intermediates and ADCs. Precise process development also requires experienced and well-trained experimental personnel, as well as suitable experimental equipment. Furthermore, to be able to conduct more experiments with less material, micro-jacketed vessels that can perform coupling experiments at the milligram scale while precisely controlling temperature have proven to be very useful, and the reaction model has been shown to be able to simulate up to several hundred liters of reaction performance. But for purification processes, gram-scale runs are needed to evaluate tangential flow filtration (TFF) conditions.
The greatest challenge in ADC drug production is the design, construction, and operation of a biomanufacturing environment that allows for the safe handling of potent cytotoxic drugs and their contaminants (e.g., transfer of toxicant-containing materials, contaminant disposal). Therefore, personnel training should be strengthened to ensure the correct use of equipment and compliance with safety concepts. A personal protective equipment plan should also be developed to cover residual risks that cannot be eliminated by engineering controls, as well as contingency plans for releases of toxic compounds. Cleaning validation of ADC production lines also requires highly sensitive detection methods. The detection of residual cytotoxins through traditional TOC and HPLC-based methods usually does not provide sufficient sensitivity, and validated ELISA or LC-MS analysis methods may be required.
Reference
