Antibody-drug Conjugate Combination Therapy Is Expected to Cure Childhood Leukemia

Comprised of a recombination monoclonal antibody and cytotoxic payloads through a linker, antibody drug conjugate (ADC) not only has a highly cytotoxic antitumor effect of small molecule drugs, but also combines the high selectivity, stability and favorable pharmacokinetic characteristics of mAb. Antibody-drug conjugates are currently a major research field, mainly focused on oncology, but in other areas such as infectious diseases are also limited. The success of this targeted drug delivery depends on many factors, one of which is the performance of the linker to release the active drug moiety under appropriate conditions.

ADC, currently in clinical trials, is mostly targeted to DNA or microtubules, and has been optimized efficiently. Due to the limited number of antigens on the tumor cell surface and the low ratio of ADC turning into tumor cells, it may fail of the merger of cytotoxic drugs clinical. auristatin and statin are the most commonly used ADC payloads by inhibiting the assembly of microtubules. Other using payloads usually are based on PBD, tubulysin, doxycycline, adrenaline, and so on. In fact, due to the intense competition, an increasing number of ADC in the early clinical trial study did not disclose the chemical structure of monoclonal antibody, payloads and ADC linkers.

Premature release of drugs can lead to systemic toxicity and lower treatment indicators. The effective linker design must balance the good stability within a few days of the cycle and the efficient cracking when delivered to the target cell. In order to enhance the solubility of ADC and dar conjugation, and overcome the resistance induced by the extracellular protein, such as MDR1, a couple of strategies are as follows.

• Conditional drug releases in the cytoplasm of target cells (cleavable and non-cleavable linkers)
• Achieving the enhancement and limitation of the bypass effect by the ability to cross the biofilm's linker and drug metabolites.
• The increase of solubility and reduction of MDR of polarity linker

ADCs are mandatory to improve the homogeneity and developability of the antibody to reduce the churn rate of drug candidates. Liquid chromatography, electrophoresis and mass spectrometry analysis technology, not only help to choose the best antibody with appropriate glycosylation characteristics of cloning, but also can be used for research and overall structure identification of a potential clinical candidate. Moreover, it can identify possibly harmful antibodies to the stability and pharmacokinetic properties. Mass spectrometry also helps to optimize the structure of the next generation mAb from a pharmaceutical perspective, allowing for the development of reduced CMC loads and better drug candidates (OptimAb) and ADC (OptimADC).

The selection of antibodies includes chimerism, anthropogenic and human antibody. The second generation ADCs all are controlled mixtures of different drug load substances, with typical average DAR of 3.5 or 4. Species with DAR greater than 4 indicate lower tolerance, higher plasma clearance, and lower body efficacy. At present most ADCs have common structural features, such as the formation of thio-succinylamide connections through the maleimide reaction of sulphide and alkyl.

But mostly a long time of ADC circulation will lead to the elimination of measurable maleic imide, which can be addressed by site-specific conjugation and alternative chemistry conjugation such as cysteine engineering, unnatural amino acids, enzyme auxiliary connections, to avoid the disintegration of retro - Michael and high payload ADC.

When it comes to the additional strategy to increase ADC efficiency, the drug design should consider avoiding potential resistance of payload, by using small protein scaffolds to enhance tumor infiltration, or through the combination of ADC and immune checkpoint inhibitor based on mAb to improve efficacy.

However, there were fewer ADC studies on non-cytotoxic drugs. For instance, ADC for the c-x-c chemokine receptor is an antigen that is selectively expressed on the serum cells.

The development of ADC benefits from the general improvements in the design of therapeutic mAb, as well as specific improvements to the enhanced homogeneity of conjugated composition methods. The diversification of ADC linker and payload provides new opportunities for improving drug transport in tumors, as well as reducing exposure to normal tissue. In fact, it is important to better understand ADC's toxic determinants, whether as a single drug or in combination with other therapies. To increase the therapeutic index, ADC needs to reduce the minimum effective dose in the efficacy of cytotoxic agents, or increase the maximum tolerable dose in tumor selectivity.

The next generation ADC relies on more homogeneous and stable ADC, and the synthesis and characterization of macromolecular structures with pharmaceutical chemical control.The recent ADC development has regenerated interest in the natural products of cytotoxicity. In the future, ADC's efficacy breakthroughs may involve payload with novel operational mechanisms. In addition, alternative forms of mAb have emerged, but they should be compared with the whole mAb in terms of toxicity, efficacy, and pharmacokinetics,

Author Bio

Established in 2004, Creative Biolabs is highly specialized in advanced antibody biochemistry and engineering. With more than a decade of exploration and expansion, our current research and service capacity covers the entire new drug discovery and development pipeline, ranging from early discovery, preclinical evaluations, cGMP manufacturing, to clinical trails. As an international cooperation, we have established offices all around the globe with more than 200 well-trained full-time scientists and technicians, who work closely with our customers and research partners to develop new medicines for a better, healthier world.

Creative Biolabs was founded by scientists who are dedicated to conquering cancer, optimizing the drug development process, leveraging accessible resources.