Enhance the homogeneity, potency, and safety of your antibody-drug conjugates (ADCs) thanks to ProteoGenix’s flexible and diversified platform. Drawing from 20+ years of experience in ADC development, our platform allies the high productivity of the XtenCHOᵀᴹ cell line with the high efficiency of click chemistry for antibody conjugation and robust bioanalytical methods. Obtain high-quality ADC products with up to 90% of antibodies conjugated with the selected DAR.
Flexible conjugation strategies
Choose between chemical (cysteine and lysine) and click chemistry conjugation methods according to your unique needs
Drug diversity and dual drug ADC development
Choose the best drug for an optimal therapeutic efficacy or opt for dual drug systems thanks to our click chemistry platform for a synergist treatment
Keep full ownership of the antibodies developed for your ADC applications
Accelerated antibody production
Seep up ADC development and antibody engineering (affinity, click chemistry…) thanks to our highly productive cell line – XtenCHOᵀᴹ
Extensive bioanalytical capabilities
Characterize DAR values, drug load distribution, % of free drug and antibody with high accuracy and precision to ensure high success rates during clinical development
Solid track record
Benefit from 20+ years of experience in antibody-drug conjugate (ADC) development a 5 therapeutic ADCs in clinical trials
Vast range of complimentary services
Streamline ADC development thanks to our flexible solutions in antibody discovery (phage display, hybridoma), engineering (affinity, stability), and stable cell line generation
I. Preliminary phase (optional)
II. Antibody-drug conjugate (ADC) development
Cleavable or non-cleavable linker
Single or dual payload
QC of the antibody by SDS-PAGE
III. Antibody conjugation
Final ADC product
Cell Line Development (optional)
ADCs consist of the following components:
These complex molecules combine the specificity of immunotherapies with the potency of cytotoxic agents. In the past decades, ADCs have found great success in the treatment of cancer, particularly, hematological conditions. With the continued improvement of linker chemistry and conjugation methods, ADCs will soon be viable tools to fight a larger number of malignancies.
Given the structure of ADCs, they are designed to target membrane-bound receptors that are abundant, specific to cancer cells, and efficiently recycled after cellular internalization. The major mechanism of action of ADCs involves the following steps:
An alternative mechanism of action relies on the release of the payload in the tumor microenvironment. With the use of cleavable linkers, it is possible to trigger the release of the payload via chemical signals, conditions, or enzymes. By releasing the payload in the extracellular matrix, cytotoxic agents are free to diffuse more quickly through solid tumors, thus averting the antigen barrier, and targeting cancer cells with significant mutations in the selected receptor (bystander effect).
Multiple strategies have been developed to conjugate linker-payload pairs to antibody carriers. The efficiency of these methodologies directly influences the load and distribution of payloads along the antibody backbone and the heterogeneity of the resulting ADC.
Chemical linkers act as the interface between drugs and antibodies in ADCs. Linkers consist of antibody-binding and a payload-binding domain. Their properties heavily influence the stability, safety, aggregation profile, therapeutic widow, and mechanism of action of ADCs.
Linkers are broadly classified as cleavable or non-cleavable. A list of the most commonly used linkers can be found in the table below.
Selecting the best linker for a specific ADC ultimately depends on several factors including the abundance of the target antigen, toxicity of the payload, and nature of the tumor (solid versus hematological tumor). For instance, cleavable linkers are more suitable when targeting low abundance target and solid tumors, given that these linkers are able to release their warheads on the tumor microenvironment allowing the rapid diffusion of the small drugs without the need for internalization.
Suitable payloads for ADCs are typically defined as efficient at killing cancer cells at the nanomolar and picomolar range. They also must be fairly soluble to avoid excessive aggregation, non-immunogenic, and possess reactive sites available for conjugation with a linker.
The major cytotoxic payloads belong to two families: tubulin inhibitors (maytansinoids, auristatins, or taxol derivates) and DNA-modifying agents (mainly calicheamicins). Most of these agents are also too toxic for system administration in a mono-therapeutic regimen. Tubulin inhibitors have an extensive and solid track record as payloads of ADCs. They act during the cell cycle, causing cell death via mitotic arrest. Most ADCs in the clinic carry tubulin inhibitors as payloads. In contrast, DNA-modifying agents can act independently of the cell growth cycle, causing the cleavage of the DNA molecule and leading to cell death by apoptosis.
More recently, alternative payloads such as camptothecin derivates and pyrrolobenzodiazepines (PBD) dimers have been gaining ground over more conventional drug classes.
What makes the bioanalysis of ADCs so challenging is the heterogeneous nature of these products – particularly relevant when conventional chemical conjugation methods (cysteine and lysine) are used. Heterogeneity is known to influence a number of ADC properties such as stability and therapeutic effectiveness, for this reason, extensive analysis of ADC products is essential to ascertain their success in later stages of development.
The major properties of ADCs and common bioanalytical methods used for their study include:
Of all the properties mentioned above, DAR and drug load distribution remain the most important. For their bioanalysis, the most widely used methods during early development include UV/Vis, HIC, and RP-HPLC, or LC-MS.
Due to the complexity and inherent heterogeneity of ADC products, it can be challenging to ensure their success during clinical development. However, focusing on optimizing a number of key properties is known to significantly increase their odds of receiving marketing approval:
Dozens of ADCs have reached the clinic since the approval of Mylotarg (gemtuzumab ozogamicin) in 2020. The current and future major cancer targets of these immunotherapeutics include:
The improvement of linker chemistry and conjugation strategies has been promoting the development of ADCs with different structures or mechanisms of action. Multiple trends are expected to mark the next generation of these complex biopharmaceuticals including:
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