Expanding the ADC toolkit with 4 critical Optimer® benefits
Optimer offers significant advantages to enhance the antibody-drug conjugate (ADC) toolkit for improved precision medicines.
ADCs – a silver bullet?
Chemotherapy is notorious for its high toxicity levels, which arise from the indiscriminate killing of healthy cells and tissues while targeting cancer cells. ADCs present new hope for precision chemotherapy by attaching highly toxic chemotherapy drugs to antibodies that can direct the drug to the specific location of cancer in the body. Targeting these drugs directly to cancer cells in ADCs aims to minimize off-target effects in healthy tissues and reduce patient side effects.
There are now 11 FDA-approved ADCs for more than 20 different indications, with a burgeoning pipeline of new molecules and conditions currently in trials.
ADCs consist of a targeting antibody, linker and chemotherapeutic payload.
The seemingly simple concept of ADCs, comprising a targeting antibody, a chemotherapy drug, and a linker between the two, belies the intricate balance required in:
- Identifying the right targets
- Refining antibody characteristics
- Balancing the dose and toxicity of the drug
- Selecting the right linkers
Leveraging a broader ADC toolkit
As research on ADCs progresses, limitations such as non-specific and insufficient payload delivery have become apparent, affecting their safety and efficacy. Common issues leading to inaccuracies in payload delivery include premature payload release, poor tumor penetration, and variable drug-to-antibody ratios.
While ADCs may not be a silver bullet, they certainly hold a valuable place among the range of cancer treatments. By expanding and refining this ADC toolkit, we can hope to advance and improve the performance of ADCs, enhancing their potential to combat a wider range of cancers with increased safety and potency.
Antibody, linker, conjugation chemistry, payload and target all represent different levers within the ADC toolkit that can be used to tailor ADC activity and efficacy. As the drug-targeting vehicle in ADCs, antibodies are crucial design levers that can be adjusted to address limitations, expand indications, and widen the therapeutic window. One effective strategy to achieve this is by using next-generation antibody alternatives, such as Optimer.
Optimer brings precision to the ADC toolkit
Optimer binders are antibody alternatives that can serve as delivery mechanisms for chemotherapeutic drugs, using the structure Optimer-linker-drug instead of antibody-linker-drug. The details matter, and some inherent characteristics of Optimer binders could enhance performance for specific cancers and expand the ADC toolkit.
Tuning specificity in discovery
For effective chemotherapy delivery, the ligand must bind specifically to the target receptor without cross-reacting with alternative targets.
Antibodies, typically developed using a host immune system, are designed to handle multiple tasks with a basic set of tools. While antibodies can be highly specific, they often exhibit cross-reactivity as an evolutionary adaptation, allowing them to function against multiple targets simultaneously. This is efficient for the immune system but not ideal for precision medicines. Researchers often engineer antibodies post-development, tweaking amino acid sequences to improve specificity. However, this process is time-consuming and can compromise other critical biophysical properties like solubility, affinity, and stability.
The Optimer platform combines protein and cell discovery processes for improved delivery vehicles.
In contrast, Optimer discovery and development is performed in vitro, providing greater control over the system. Target specificity is built into the discovery process, with cross-reactive targets included and any interacting binders eliminated. Plasma and serum are incorporated into the discovery phase to support stability and binding analysis, ensuring the final isolated binder meets the required profile. Also, Optimer discovery can be carried out across protein and cell targets – using both in the process ensures that the required selectivity is achieved to the protein biomarker and then further enhanced in the cell-expressed form.
Improved activity in the tumour microenvironment
To increase the specificity of ADC delivery and prevent premature payload release, techniques such as tuning the pH performance of Optimer binders can be employed. This is crucial when the target receptor is highly expressed on cancer cells but present at low levels on healthy cells, which can cause the ADC to unload the chemotherapy cargo into the wrong cells, resulting in toxic side effects.
The tumor microenvironment (TME) has a high redox environment with altered pH compared to standard tissues. Optimer discovery can incorporate pH restraints, selecting binders with higher target affinity that bind more strongly under low pH conditions. Adding this performance to the ADC toolkit could help ADC performance where it is needed in the TME.
Another approach involves masking the receptor binding site of the Optimer with a cleavable fragment susceptible to enzymes highly expressed in the TME, such as fibroblast activation protein alpha. Once in the TME, these enzymes can cleave the paratope mask of the Optimer, allowing it to interact with the receptor and deliver the chemotherapy precisely to its site of action.
By optimizing these methods, Optimer binders can significantly improve the performance and specificity of ADCs in cancer treatment.
Moving ADCs to the middle of solid tumours
Optimer binders are approximately ten times smaller than antibodies. Their smaller size means they can better penetrate the dense mass of cancer cells to deliver chemotherapy to the centre of solid tumours, a problem that has plagued ADCs.
EpCAM aptamer penetrates the tumoursphere more effectively than EpCAM antibody. (Xiang et al, 2015)
By leveraging these approaches, Optimer binders can significantly enhance the performance and specificity of ADCs in cancer therapy. For blood-borne cancers, high affinity in target binding, whether from an antibody or an Optimer, is often preferable. However, for solid tumors, a lower affinity may facilitate better penetration through the tumor mass. The ability to fine-tune Optimer affinity during the discovery process, combined with their small size, can optimize delivery of toxic treatments directly into the tumor core.
Ensuring Consistent and Stable DAR
Consistency in drug-antibody ratio (DAR) is a significant challenge in ADC development. Early strategies involved conjugating the linker-chemotherapy structure to amine residues on antibodies. However, the numerous available amine residues make controlling drug localization and quantity challenging, necessitating extensive post-conjugation standardization.
Alternative approaches have explored using disulfide linkages, but this method risks disrupting the antibody’s structural disulfide bridges, potentially damaging the antibody and requiring further standardization. Stabilizing internal disulfide bridges in antibodies for more stable thiol conjugation has been attempted, but excessive stabilization can prevent natural degradation and lead to hepatotoxicity due to antibody accumulation in the liver.
Site-specific linkers using click chemistry to attach payloads to antibody glycan groups present a promising solution. These glycans are consistently positioned across antibodies, potentially allowing controlled loading without interfering with glycan function, which is crucial for antibody stability.
Optimer offers flexibility with site-specific conjugation using diverse chemistries, allowing for precise drug loading without interfering with Optimer function. The absence of inherent amine or thiol groups in Optimer means that chemistries for drug loading can be added selectively, improving drug loading strategies and reducing the need for extensive manufacturing standardization.
As ADCs continue to evolve, next-generation antibody alternatives like Optimer could enhance the ADC toolkit, offering new, tailored therapies for a broad range of cancers and targets.
If you would like to discuss your needs to see how Optimer could help break down the scientific barriers to your research success, get in touch with the team today.