Antibody-drug conjugates (ADC) are one of the fastest-growing anticancer drug segments, linking the targeting prowess of monoclonal antibodies with the cell-killing capabilities of a cytotoxic payload.
As a drug class, the advantage of ADCs is their ability to target and kill tumor cells while leaving healthy cells alone. Interest in this class of drugs is high. A Molecules review in 2021 shared that there were 80+ ADCs in clinical development, with 11 already approved for use by the FDA.
While interest is high, so is complexity. From the development & manufacturing perspective, ADCs are not simple compounds. The challenge in their design stems from the range of inputs and steps which must be considered and optimized:
- Selecting the right target
- Choosing a mAb
- Identifying the cytotoxic payload
- Developing the antibody-payload link, and more.
What Is an Antibody-Drug Conjugate?
An ADC consists of a monoclonal antibody linked to a specific drug. The drug helps carry the antibody to the target source, after which the antibody itself binds to the target. Once the antibody binds to the target, the drug enters the target – killing it without harming the surrounding cells. This targeting capability allows ADCs to be used to address a variety of illnesses, including cancer.
Choosing the Right Antibody to Link to the Drug
For the ADC to be effective, choosing the right antibody is critical. Some of the most popular options include IgG1 and IgG4. Key factors to consider when selecting your mAb include:
Binding Affinity
The antibody you select must effectively bind to the target antigen. The monoclonal antibody you choose – if you are targeting CD30 for example – might not be the same as the antibody you would choose if targeting CD33.
There are different ways you can measure the binding affinity of a specific antibody. Popular techniques include flow cytometry or an ELISA, and affinity for the antigen is usually measured when the antigen is in the native conformation.
Antibody Internalization
Next, you need to measure antibody internalization. This refers to the degree that the antibody will be internalized by target cells. Antibody internalization is important because it can help you get the drug into the target cell, which significantly improves efficacy.
There are different ways you can measure antibody internalization with an ADC. Flow cytometry is again a common technique. It can also be combined with various radio labeling techniques and imaging to make sure the antibody will be internalized by the target.
Antibody Location
The entire purpose of the antibody is to deliver cytotoxic cargo to the final source. Therefore, we need to track the location of the antibody and make sure the drug is released in the appropriate intracellular environment. There are various ways we can monitor the location of the antibody once it has been ingested by the target cell, including confocal microscopy and flow cytometry. These tools and techniques can track and determine the final status of the ADC once it has been internalized, making sure the therapeutic cargo has reached the right source.
The Top Benefits of Using ADCs
While there are some hurdles to ADC process development, the investment in time (and the right development partner) makes antibody-drug conjugates well worthwhile. Some of the top benefits of ADCs include:
Larger Therapeutic Window
With traditional treatment options, the therapeutic window is relatively narrow. The difference between a therapeutic dose and a potentially dangerous dose tends to be relatively small. With ADCs, the therapeutic window is significantly expanded because linker chemistry provides greater degrees of tolerability and safety. For this reason, ADCs can carry larger amounts of cytotoxic drugs without increased side effects.
More Cytotoxic Medications with Fewer Side Effects
As mentioned above, ADCs can carry larger loads of cytotoxic medications with fewer adverse side effects, which creates a more effective treatment option. Because ADCs have more cell-killing potential, they could lead to improved treatment outcomes.
Increased Selectivity and Specificity for Tumors
The biggest reason why ADCs do not generate as many systemic side effects is that they have more selectivity and specificity for the tumors and cells they target. Because antibodies have been specifically designed to bind only to a specific antigen, it is possible to deliver the treatment dose directly to the target without harming other cells in the process. This provides greater drug tolerability and reduces potential systemic exposure – all of which reduces potential side effects.
These potential benefits have been a key driver in the market for ADCs and biosimilars, with demand continuously rising. One commonality among successful ADC projects? Partnering with the right CDMO. An experienced team can guide the way and support you with the necessary infrastructure, expertise, and connections in place to navigate this emerging market from start to finish.
LGM Pharma & ADCs
Recently, we were approached to source a mAb for a startup biopharmaceutical company with a novel, patented ADC technology designed to enhance the effectiveness of the antibody drug conjugate. As a startup, the client lacked supply chain experience, and did not have the capability to formulate and manufacture the ultimate drug product.
LGM not only sourced the mAb, but also identified a partner who could perform the formulation and manufacturing of the final ADC drug product on the client’s behalf. Today, LGM manages the logistics of the client’s entire supply chain – from API sourcing through drug product formulation and bulk production.
Partnering with the right CDMO is absolutely crucial, as an experienced team can guide and support your ADC project with the necessary infrastructure, expertise, and connections to navigate this emerging market.
Contact Us if you’d like to discuss an antibody drug conjugate, monoclonal antibody or biosimilar project!