Adding Optimer? to the ADC toolkit

Antibody-drug conjugates (ADCs) are emerging as a precise tool in the battle against cancer, offering targeted destruction of cancer cells with minimal side effects. As we continue to refine these molecules, next-generation ligands like Optimer can further enhance their precision and adaptability, customizing their use for specific diseases, targets, and payloads.

ADCs – a silver bullet?

Chemotherapy is known for its high toxicity levels, which result from killing healthy cells and tissues while pursuing cancer cells. Antibody-drug conjugates offer a new hope for precision chemotherapy by tagging the highly toxic chemotherapy drugs with antibodies that can guide the drug to the specific location of the cancer in the body. Targeting these drugs directly to cancer cells aims to reduce off-target effects in healthy tissues and reduce patient side effects.

There are now 11 FDA-approved ADCs on the market for more than 20 different indications and a burgeoning pipeline of new molecules and conditions in trials.

The seemingly simple concept of ADCs consisting of a targeting antibody, a chemotherapy drug, and a linker between the two, does not account for the delicate balance required in:

-??????????? identifying the right targets

-??????????? refining antibody characteristics

-??????????? balancing the dose and toxicity of the drug

-??????????? selecting the right linkers

Leveraging a broad ADC toolkit

As research progresses, limitations such as non-specific and insufficient payload delivery have become apparent, impacting the safety and efficacy of ADCs. Common reasons for inaccuracies in payload delivery include premature payload release, poor tumour penetration, and variable drug-to-binder ratios.

So ADCs might not be a silver bullet, but they certainly have their place within the toolkit of cancer treatments, and by adding to this toolkit, we can hope to advance and improve their performance. ??

As the drug-targeting vehicle in ADCs, antibodies represent one of the design levers that can be pulled to address these limitations, expand indications, and widen the therapeutic window. One way to achieve this is using next-generation antibody alternatives, like Optimer.

What can Optimer bring to ADCs?

Optimer binders are antibody alternatives that can be used as a delivery mechanism to target chemotherapeutic drugs, using the same overall structure of Optimer—linker—drug rather than antibody—linker—drug. But as ever, the devil is in the details, and some of the characteristics inherent to Optimer binders could yield improved performance for specific cancers, and add to the ADC toolkit.

Specificity tuned with discovery

When developing chemotherapy delivery vehicles, the ligand must bind specifically to the target receptor without cross-reactivity to alternative targets.

Antibodies are typically developed using a host immune system, which has cleverly crafted ways to do multiple jobs using one basic set of tools. While antibodies can be exquisitely specific to their target, cross-reactivity is often built-in as an evolutionary optimum so that they can function against multiple targets in parallel. This saves the immune system energy in producing multiple binders, when one can do the job of many.

Obviously, this isn’t what we want in our precision medicines, and researchers have worked out ways to engineer the antibodies post-development, tinkering with the specific amino acid sequences to achieve specificity. But this takes time and is often a trade-off with other biophysical properties essential to development, like solubility, affinity, and stability. ?

In comparison, Optimer discovery and development is performed in vitro, allowing control over the system. Target specificity is built into discovery, with cross-reactive targets included and any binders that interact with these removed. Plasma and serum can be included in the discovery process to support stability and binding analysis and ensure the final isolated binder has 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 replicated in the cell-expressed form.

New activity in the tumour microenvironment

To increase the specificity of delivery and prevent premature payload release, methods like tuning pH performance of Optimer binders can be used. This may be necessary when the target receptor is expressed highly on cancer cells, but 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 to treatments. ?

The tumour microenvironment (TME) is a high redox environment, so has altered pH compared to standard tissues. Optimer discovery can include pH restraints, selecting for binders with higher target affinity and binding more strongly under low pH conditions.

Another option could be to mask the receptor binding site of the Optimer with a cleavable fragment that is susceptible to enzymes highly expressed in the TME, like fibroblast activation protein alpha. Once in the TME the presence of such enzymes could cleave the paratope mask of the Optimer allowing it to interact with the receptor and delivery the chemotherapy to its site of action.

Slipping to the centre of solid tumours

Optimer binders are approximately ten times smaller than antibodies. Their smaller size means they can more easily penetrate the dense mass of cancer cells to deliver chemotherapy to the centre of solid tumours, a problem that has plagued ADCs.

High affinity in target binding from an antibody or Optimer is often preferable for circulating tumour cells in the treatment of blood-borne cancers. However, for solid tumours a lower affinity might be best to help penetrate the mass. Being able to tune Optimer affinity within the discovery process, and pairing this with the small size of Optimers, can offer an ideal solution to get to deliver toxic treatments right into the heart of tumours. ?

Consistent and stable DAR

Consistency in drug-antibody ratio is a problem that is being tackled in several ways. Initial strategies involved conjugating the linker-chemotherapy structure to amine residues on the antibody. However, the multitude of available amine residues makes it challenging to control the drug’s localization on the antibody and the number of drugs it carries, requiring extensive post-conjugation standardization.

Other options have examined the potential of using disulphide linkages. However, antibodies rely on disulphide bridges for their structure, so there is the potential to rip the molecule in half with this method, wasting valuable antibody and again requiring extensive downstream standardization of the drugs.

Some have looked at stabilizing the internal disulphide bridges for antibodies to allow more stable and targeted thiol conjugation. Still, excessive stabilization of antibody bridges can prevent natural degradation in the body, leading to hepatotoxicity through a build-up of the antibodies in the liver.

Site-specific linkers that use click chemistry to add payloads to antibody glycan groups could offer a good alternative. The antibody glycans have been maintained at similar positions across all antibodies. These linkers could potentially allow controlled loading but must be sure not to intervene with the function of the glycan group, which is often vital for antibody stability.

Optimer offers site-specific using diverse chemistries to allow for different conjugation strategies. These chemistry groups for conjugation can be added to the Optimer at specific sites. A lack of inherent amine or thiol groups within Optimers means that any addition of these chemistries for drug loading is specific and does not interfere with Optimer function for improved drug loading strategies and reduced manufacturing standardization requirements.

?

ADCs continue to gain traction, and more variations are entering the pipeline. To optimize these molecules for a broader range of cancers, next-generation antibody alternatives like Optimer could offer new and improved components that can add to the ADC toolkit to build a plug-and-play collection of tailored therapies for multiple diseases and targets.