Patient benefit from ADCs is limited by off-target toxicities.
The fundamental problem is that less than 1% of the dose administered binds to the tumor.1 The other 99% is broken down by normal tissues following the elimination pathway of the binder. The binder and the payload are attached so when the ADC is eliminated by normal tissues, the linker between the binder and the payload is broken. This is known as catabolic activation, which leads to normal tissue exposure to a toxic payload. Clinical data show that this problem is not fixed by more stable linkers.2,3
Shasqi has solved this problem with our Click Activated Protodrugs Against Cancer (CAPAC) pre-targeting platform.
CAPAC separates the binder from the payload and uses click chemistry, a novel technology that won the 2022 Nobel Prize in Chemistry, to reunite the two at the tumor. Click chemistry is the ideal reuniting technology: it is rapid, covalent, non-immunogenic, and highly selective.
Shasqi is the first company to use click chemistry in vivo.
The key to avoiding off-target toxicities is to administer the binder first, a process known as pre-targeting.4
The clickable binder attaches to antigens at the tumor. As with ADCs, about 1% binds to the tumor and anything that doesn’t bind to the tumor is cleared by normal tissues, there is no catabolic activation because there is no payload attached to the binder to activate.
Next, we infuse a clickable inactivated payload. It is only when it finds the clickable binder at the tumor, that the toxicity is activated, via an in vivo click chemistry reaction. As with ADCs, only 1% reaches the tumor. Anything that doesn’t click with the binder at the tumor remains inactive and is cleared by normal tissues. There is no catabolic activation, because the clickable payload can only be activated in the presence of the binder at the tumor.
Pre-targeting eliminates catabolic activation and decreases dose-limiting toxicities. This allows more drug to be given, unlocking unrealized clinical benefit.
The binder carries no payload so more binder can be given. This allows more receptors on the tumor to pair with a binder, increasing antigen occupancy and delivering more drug to tumor.
We have created high ‘Drug Antibody Ratio (DAR)’ binders by adding multiple click chemistry components to the binder. This concentrates toxic cancer drugs at the tumor without the toxicity penalty seen when you increase the DAR on an ADC.
Because CAPAC can use smaller formats for binding so you can maximize tumor penetration.
Click chemistry enables activation independent on the biology of the cell.
CAPAC can activate payloads at receptors that do not internalize, expanding the number of targets that can be drugged.
Activation without internalization also overcomes potential mechanisms of resistance.
We can give a binder and follow this with a clickable diagnostic radioisotope to understand where the binder finds its target in the body.
This can then be followed with another course of the binder followed by a clickable payload. The payload can be either a therapeutic radioisotope, a small molecule cytotoxin or other payload classes (e.g. immune stimulants, degraders, etc).
It is possible to localize an antigen-targeting activator at the tumor and use it to activate any one of our protodrugs.
This creates the opportunity to cycle through different payloads over the patient’s journey.
It allows for the administration of combinations of different payloads with complementary mechanisms of action during a treatment cycle.
We have clinically validated the specificity and safety of CAPAC in patients with advanced soft tissue sarcoma and demonstrated proof of concept with one of our assets, SQ3370. This activates a doxorubicin protodrug at the tumor with an intratumorally injected biopolymer.
In our phase 1 study, SQ3370 was well-tolerated with no dose-limiting toxicities, even in patients receiving >15x the conventional dose-equivalent of doxorubicin per cycle.
Importantly, we showed that our technology works inside human patients: the protodrug was inert until activated, and there was rapid release of active doxorubicin at all doses levels with increasing exposure, consistent with selective activation.
1. Mechanisms of Resistance to ADCs. LoRusso, P; ASCO 2024 presentation.
2. Herrera A. et al., 2022 Clin. Cancer Res.
3. Polanca-Wessels M. et al., 2015 Lancet.
4. Verhoeven et al., 2019; Therapeutic Applications of Pretargeting, Pharmaceutics
