José Mejía Oneto, PhD, Founder and CEO at Shasqi, discusses the potential of chemistry to engineer biology to improve the effectiveness of human therapeutics and revolutionise the treatment of disease.
What if we could control exactly where drugs went in the body? And by doing so make them much more effective with little to no side effects? That may just be possible with a powerful new technology known as click chemistry.
In October 2022, Drs Carolyn Bertozzi, Barry Sharpless, and Morten Meldal won the Nobel prize for Chemistry for the development of click chemistry and bioorthogonal chemistry. This simple and elegant chemistry concept has the potential to revolutionise how we treat disease.
Click chemistry is a technology in which two compounds ‘click’ together via an irreversible chemical reaction, like clicking a seatbelt into a buckle. The concept was first described by Dr Sharpless in 2001 and further refined by Dr Sharpless and Dr Meldal (working independently) in 20041. Dr Carolyn Bertozzi took click chemistry to a new level by developing click reactions that work inside living organisms without disrupting the normal chemistry of cells2. She achieved this by removing the copper catalyst required by the first click reactions, but incompatible with living cells or organisms. In these bioorthogonal reactions –the term for click chemistry in living organisms – the two molecules in the reaction click with each other, ignoring everything else around them. It is the intersection of click chemistry with biological systems that holds so much promise for drug discovery. Applying click chemistry to therapeutics has the potential to not only improve the safety of existing drugs, but to significantly enhance their efficacy by activating the therapeutic precisely at the area in the body they are needed and potentially unlock new biological effects. Only 1% or 2% of the dose of a drug administered to a patient goes to the desired target site in the body. This is true for any drug administered, whether it is a century-old pain medication or the latest cancer treatment. If we could make this more precise, we could increase the therapeutic index of drugs, making them more effective with fewer toxicities. The exploration of the transformative potential of click chemistry begins in cancer therapeutics. Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. The toxicities associated with cancer therapies are significant. These side effects not only contribute to a lower functional status and quality of life but can also lead to delays and discontinuation of therapy that decrease treatment effectiveness and increase the morbidity and mortality of the disease3.
We’re exploring the potential of click chemistry. Through a modular platform known as CAPAC (Click Activated Protodrugs Against Cancer), we are precisely targeting the therapies to the tumour site. CAPAC is made up of two components: one part is localised to the tumour, either through direct injection of a biopolymer into the tumour or by using an antibody that binds to a receptor expressed by the tumour cell or microenvironment. A cancer therapeutic (or payload) is coupled to the other part, leading to an attenuated version of the initial drug. This ‘protodrug’ is infused into the body. The two components then ‘click’ together at the tumour site, releasing the active version of the cancer therapeutic directly into the tumour and the surrounding tumour microenvironment. A tumour targeting agent can activate any payload and vice versa. Any payload can be activated by different tumour targeting agents.
We are exploring the safety and efficacy of CAPAC with Shasqi’s lead asset, SQ3370, which couples click chemistry with the chemotherapeutic agent, doxorubicin. Doxorubicin is an effective anti-cancer drug widely used for the treatment of solid tumours and haematologic malignancies in both adults and children. However, doxorubicin is associated with acute myelotoxicity as well as cumulative and dose-dependent cardiotoxicity. The cardiac issues can range from minor changes in myocardial structure to congestive heart failure and cardiomyopathy that can result in the need for heart transplant or even death. These side effects limit the dose of doxorubicin that can be given in an individual cycle as well as limiting the dose that can be given over the lifetime of the patient.
By coupling doxorubicin with click chemistry in CAPAC, we hope to limit these toxicities and allow higher doses to be active at the site of the tumour. We have shown in animals that unprecedented doses of doxorubicin can unlock new biological effects; in 2021 we published a manuscript showing that if you inject a single tumour in a mouse with two tumours, both tumours will shrink due to systemic immune activation4.
Early clinical data with SQ3370 are promising. During a Phase I study, patients were able to safely receive more than 12 times the conventional dose of doxorubicin without experiencing dose limiting toxicities5. Encouragingly, preliminary data in humans is consistent with the non-clinical findings showing an increase in activated immune cells at the injected tumour and signs of tumour cell death on sequential tumour biopsies taken from patients in the study5. This suggests that treatment can stimulate the expansion and activation of the immune tumour-fighting cells that matter. An ongoing Phase II clinical trial is evaluating the safety, tolerability, and ability of SQ3370 to shrink solid tumours and extend survival.
This is just the beginning of what click chemistry can do. We are currently building a library made up of cancer therapeutics with different mechanisms of action, and tumour targeting agents. After a single tumour targeting agent has been created it can be tested with different cancer therapeutic payloads, each with a unique mechanism of action. This enables faster development timelines. Multiple cancer therapeutic payloads can also be used with a single tumour targeting agent either in sequence or even at the same time. The use of multiple cancer therapies at any one time is currently limited due to the overlapping toxicities of the cancer therapies. We expect click chemistry to unlock this opportunity for the field.
We are also developing different modalities for tumour targeting. We have tested tumour targeting agents that are directly injected into the tumour with a biopolymer. Building on the success of antibody-drug conjugates (ADCs), we are also creating tumour targeting agents that are biologics which bind to a specific antigen on the tumour cell or in the tumour microenvironment. One aspect that elevates our approach above traditional ADCs is the removal of the need to be internalised and metabolised. This confers a second benefit: as long as there is antibody-bound click chemistry activator at the tumour, a cancer therapeutic payload can be administered over multiple consecutive days, which has the potential to be more potent than a single ADC dose administered every two or three weeks.
Click chemistry could also be applied to the development of bispecific immune cell engagers that have less toxicity with a broader range of tumour specificity. It could also be used to localise cytokines to cold tumours to activate an immune response, or radiotherapeutics to enhance cancer cell death. The possibilities are vast.
DDW Volume 24 – Issue 2, Spring 2023
References
- Kolb, Finn, Sharpless, Angew. Chem. Int. Ed. 2001, 40, 2004-2021.
- Baskin, Prescher, Laughlin, Agard, Chang, Miller, Lo, Codelli, Bertozzi. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16793-7.
- Cancer moonshot blue ribbon panel report. (2016). pp. 33-35. https://www.cancer.gov/research/ key-initiatives/moonshot-cancer- initiative/blue-ribbon-panel/blue- ribbon-panel-report-2016.pdf
- Srinivasan, S. et al., (2021), Adv. Therap., 4: 2000243.
- Chawla et al., (2022) Annals Onc., Vol 33, supplement 7, S123.
About the author:
José Mejía Oneto, Founder and CEO of Shasqi, has a background in orthopaedic surgery and organic chemistry. As a clinical stage biotech company, Shasqi is using its Click Activated Protodrugs Against Cancer (CAPACTM) platform to maximise the efficacy of oncology therapies using Nobel Prize winning click chemistry technology.
