(MENAFN- Hunan Huateng Pharmaceutical Co Ltd) Structurally, an ADC consists of monoclonal antibodies (Antibody) that target specific antigens on tumor surfaces, cytotoxic drugs (drugs) that kill tumor cells, and linkers (Conjugate/ linkers) that conjugate cytotoxic drugs to antibodies.
The link between the antibody and linker is controlled by the coupling method, which determines the DAR value of the drug and affects the stability and PK characteristics of the ADC. The connection of Linker to the drug is controlled by a shearable/non-shearable technique that determines the properties of the active payload, the rate at which the payload is released, and affects the solubility, stability, and titer of the ADC.
Optimization of Antibody: Development of new targets and dual antibody ADCs
The selection of antibodies is the starting point for the design of an ADC, and the antigenic target is the vehicle through which the ADC recognizes tumor cells. Considering that targets play a key role in delivering drugs to cancer cells, it is important to develop new targets or ADCs to expand new indications and gain a larger market space. Currently, a number of innovative ADC drug targets have entered the clinical stage worldwide.
In the process of research and development of innovative targets, it should be noted that the antigen targets suitable for ADC drugs should have the following characteristics:
It is highly expressed in tumor cells and low or no expression in normal tissues.
It is expressed on the cell surface and can access antibodies in the circulatory system.
It should internalize the antigen to allow the ADC drug to enter the cell after binding.
In addition, unlike traditional monoclonal ADCs, newly developed bi-specific ADCs can simultaneously target two different antigens, potentially increasing the rate of antibody internalization or improving tumor specificity (Figure 5). For example, the novel bi-specific ADC ZanidatamabZovodotin (ZW49) uses the internalization of Zanidatamab-enhanced antibody HER2 to deliver a novel cytotoxic drug to tumor cells via the slicable linker, inducing tumor cell death. Studies have shown that its efficacy and safety are good.
Optimization of Drug: continuous optimization of payload drugs
The cytotoxic payload carried by an ADC is the most important effector component, also known as the payload. It binds to key targets such as microtubules or genomic DNA to inhibit tumor cell proliferation. In order to develop more effective payloads, a number of relevant studies are under way, which can be optimized from three aspects: physical and chemical properties, load quantity and new loads.
Optimizing the physical and chemical properties of the current payload, especially the polarity, can overcome some of the problems faced in ADC preparation and application. Studies have shown that attaching too many hydrophobic payload molecules changes the conformational stability of the antibody, which increases its tendency to aggregate and precipitate, and ultimately affects the maximum DAR. At the same time, hydrophobic payloads can easily penetrate cell membranes and kill surrounding antigen-negative tumor cells through bystander effects. By contrast, hydrophilic payloads spread cancer cells more slowly and reduced bystander influence. Therefore, the hydrophilic polyethylene glycol (PEG) is used to balance the hydrophobic load and improve the overall stability of the ADC.
Most cancer treatment regimens require the use of multiple drugs, and clinical ADCs contain only a single drug payload. Therefore, it is imperative to develop ADCs containing multiple payloads. A study of a dual-payload ADC targeting HER2, consisting of a DNA crosslinking agent PNU-159682 and a tubulin polymerization inhibitor monomethyllaurin F (MMAF), showed that PNU-159682 induces S-phase cell cycle arrest through DNA damaging activity. By inhibiting tubulin polymerization, MMAF also causes G2/ M phase cell cycle arrest, indicating that the dual-payload ADC has a dual killing mechanism of tumor cells. In addition, dual payloads with two unrelated mechanisms may achieve mechanism synergies and minimize cancer cell resistance.
The development of new payloads has always been a hot topic in ADC design and cancer chemotherapy research. Structural modifications to approved payloads or well-studied toxins are currently considered to allow faster identification of new payloads. In addition, some new compounds may be able to combine two targets as dual-targeted warheads.
Optimization of Conjugate: Active linker can create more drug configurations
Linkers are divided into cleavable linkers and non-cleavable linkers. Research focuses on the preparation of homogeneous ADCs using connector technology, developing connector technologies that can easily connect antibodies to their payloads, and finding new ways to improve DAR while maintaining homogeneity. At present, some new connector technologies are under test, including secondary bridging ADC, DNA bridging ADC, self-assembly ADC, high DAR ADC, and optical shear ADC.
In summary, many preclinical studies have innovated to improve therapeutic efficacy or overcome the shortcomings of existing ADCs, thus inspiring the field of antibody drug conjugates and expanding the forms of development.
These novel antibody drug conjugates include, but are not limited to, small molecule conjugates (SMDCS), antibody drug conjugates, peptide-drug conjugates (PDC), amphiphilic peptide-drug conjugates, amphiphilic inhibitor-drug conjugates, antibody-polymer-drug conjugates, antibody-photosensitizer conjugates (APCs), and ligand drug conjugates (LDCs).
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