When we get an ideal candidate for ADC, the next step is to consider how to scale it up. This step is important because it is directly related to the post-market market of drugs. Mature and simple synthesis methods will further reduce the cost of drugs.
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Drug-to-antibody Ratio (DAR)
The average number of cytotoxic drugs linked to each antibody is drug-to-antibody ratio (DAR). When the DAR is larger, the metabolic rate of ADC drugs increases, the half-life decreases, and the systemic toxicity increases. Ideally, when the DAR is 4, the curative effect of the drug is the highest. Therefore, in the actual production, the drugs with DAR less than 2 or DAR greater than 4 are removed by quality control and purification process to ensure the uniformity of drugs. Creative Biolabs’s ADC technology can insert cysteine residues at specific sites and then conduct site-specific conjugation with cytotoxic drugs to obtain high homogeneity products.
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Five Key Quality Factors
- DAR
Potential adverse effects: Toxicity, pharmacokinetics, and safety
Improvement direction: DAR is directly controlled in the production process, therefore its variation range should be reduced.
- DAR species composition
Potential adverse effects: Toxicity, pharmacokinetics, and safety
Improvement direction: Drugs may have strong heterogeneity, thus the DAR consistency should be maintained between batches in production.
- Free drugs
Potential adverse effects: Security
Improvement direction: Free drugs may increase systemic toxicity and need to be removed
- Polymers or fragments
Potential adverse effects: Immunogenicity, pharmacokinetics, and toxicity
Improvement direction: The direction of process improvement is to prevent the formation the polymers, which may be due to the hydrophobic aggregation of the linked drugs and reduction/oxidation reaction.
- Residual solvents
Potential adverse effects: Security
Improvement direction: The solvent is used to dissolve small molecule drugs when antibodies are conjugated and removed when the reaction is finished
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Antibody Conjugation Technique
ADC techniques have experienced three generations, which greatly widen the treatment window. The small molecule toxicity of the first generation ADC is not strong enough, and the ADC is not stable enough, so most of them end in failure. The second generation of drugs uses more toxic small molecules to overcome the weak efficacy of the first generation. However, because the traditional chemical conjugation method is still used, the uniformity of DAR is poor (0-8 or more) and the linker stability is not satisfying. So, it is easy to cleave in the blood, causing serious side effects. At present, two second-generation ADC drugs have been approved for marketing (Adcetris and Kadcyla). The birth of the third generation of ADC drugs is mainly due to the development of site-specific conjugation techniques, such as unnatural amino acid conjugate and enzyme-catalyzed conjugate. More accurate conjugate techniques can control the location and number of highly active drug molecules conjugated on antibodies. The heterogeneity of ADC will directly affect its distribution and metabolism in vivo, so the higher homogeneity will improve drug purity and quality control.
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Scale-up production of ADC drugs
ADCs need to use highly toxic and highly active cytotoxic small molecular as loading drugs. In the production of ADCs, all weighing, reaction, and quality control operations involving highly active cytotoxic drugs need to be protected by equipment such as isolators, so as to avoid the diffusion of aerosols from these small molecular drugs and to avoid polluting drugs. In addition, it is also necessary to do a good job in personal protection and training staff.
The use of disposable materials and consumables in the production of antibody-coupled drugs will greatly reduce the production cycle and increase flexibility, so disposable materials and consumables will be more and more widely used in the production of this kind of drugs. Because a certain proportion of organic solvents are usually used in the production of ADCs, so the materials used in drug production (such as disposable reaction bags, ultrafiltration membrane packages, pipelines, etc.) need to be able to tolerate organic solvents and the extractables and leachables of the materials need to meet the requirements of regulations, but in the long run, the production cost is high, and the balance between production cost, efficiency and benefit needs to be comprehensively considered.