Over the years there have been major challenges in the development of antibody-drug conjugates (ADC), including: choosing the right target, right antibody, right linker, right drug, and the right patient. With multiple variables, the possible combinations can be seemingly endless.
Here are some of the challenges we face today:
- Hydrophobic drug payloads are more easily recognized and cleared by the immune system, often leading to dose-limiting toxicities, including neutropenia, liver toxicity and eye toxicity.
- High drug loading of hydrophobic drug can lead to such toxicity. There has been much progress in the last 5 years in the development of novel methods to control the drug-to-antibody ratio (DAR) loading using site-specific conjugation technology. Now it is routine to produce single peak purity ADCs with only two drugs per antibody with a very tight distribution, and no detectible 0 or 4 drug loaded species.
- Unstable attachment of the drug linker to the protein can cause potential free drug exchange or release leading to dose-limiting toxicity.
- Cleavable drug linkers need to be stable in serum, with a stable DAR profile after lengthy incubation with serum enzymes.
- Payload needs to be appropriate, whether membrane permeable for bystander killing, or not. The mechanism of action needs to be appropriate for the cancer cell type in particular.
There are some common learnings that can help overcome these challenges. Modern ADC design incorporates these design features into the attachment, linker and payload components of a successful ADC molecule.
Modern payloads have been made more easily soluble, either by either modifying payload functional groups themselves, providing a solubilizing linker, or using a hydrophilic polymer backbone approach.
Unstable maleimide attachment has been mostly solved through a variety of means including base-catalyzed hydrolysis, as well as switching to the bromo or iodoacetamide versions of the same payload linker. The plethora of alternative chemistries available allow for a stable covalent attachment of the drug linker to the protein.
The variety and diversity of payloads available today is truly amazing. There are many various mechanisms of action available beyond the simple tubulin inhibitors or DNA damagers. This allows for the modern development of dual-payload ADCs using orthogonal mechanism of action payloads.
It can be argued that single ADCs applied together might be a better approach clinically, but a dual labeled ADC is a scientifically interesting concept that should be further developed. Various stoichiometries can be used to balance varied potencies of chosen payloads.
Recent improvements in linker solubility, as well as the choice of a less potent TOP-1 class of payload, have led to the development of several modern, hydrophilic DAR 8 ADCs, including the Diiachi-Sankyo’s trastuzumab deruxtecan (DS-8201) and the Immunomedics’ sacituzumab govitecan (IMMU-132).
Seattle Genetics has pushed the boundaries of the possible with their SGN-CD48A molecule, with has all in one molecule: stable attachment, solubilizing PEG side chain, glucuronide sugar solubilizing and cleavage, and DAR 8 loading of MMAE.
Mersana’s Dolaflexin platform uses a hydrophilic polymer to achieve a high DAR loading of 12-15 of an auristatin payload (auristatin F – hydroxypropylamide or AF-HPA). Despite the analytical and manufacturing challenges, this continues to be an interesting approach, and their new Dolasynthen platform may bring further improvements.
Important improvements in the development of DNA-interactive payloads have taken place, including Femtogenix’s pyrridinobenzodiazepine (PDD) platform. This platform allows a toolbox approach to payload selection through the availability of payloads with multiple mechanisms of action (i.e., DNA mono-alkylating and cross-linking) and multiple potencies (i.e., from nM to pM), thereby allowing the production of ADCs with a very favorable therapeutic window.
LegoChem Biosciences has a novel technology that uses an improved glucuronide sugar as a solubilizing protective group on the PBD payload. Their pro-drug approach creates a payload that is more than ~100x more safe as a free drug than the de-protected payload. This may allow for a much better safety profile for their LCB-17 drug candidate compared with standard pyrrolobenzodiazepine (PBD) payload ADCs.
Another important industry trend is the increase in the number Contract Development and Manufacturing Organizations (CDMOs). Ten years ago there were but a handful of places that could manufacture antibody-drug conjugates (such as Lonza and others). Today there are more than 40 CDMOs of all shapes and sizes.
Furthermore, the technical expertise exhibited these by CDMOs is truly impressive, with many companies offering their own proprietary, site specific, conjugation technology to clients.
New horizons for future ADCs may include bi-functional antibody scaffolds that can allow for either bi-paratopic antigen recognition or immune-cell recruitment. New payloads are being implemented that are immunomodulatory, with up-regulating or down regulating local immune function.
One thing is clear, the ADC industry is moving quickly, is learning from past lessons, and is poised for great developments in the near future. My job is to help clients achieve their ADC development goals quickly and efficiently by pointing the way to the latest and best technologies available for advanced ADC design.
This is an excerpt from Rick Powers course: Workshop A – Advanced Design of ADCs: Principles and Applications with Next Generation Linkers and Site-Specific Technology, which he taught at the Hanson-Wade’s World ADC meetings held in the United States, Asia, and Europe.
References
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Article DOI: 10.14229/jadc.2019.10.23.001
