A collaborative effort involving TIDE, AbbVie, and Calico Life Sciences has led to the creation of a novel molecule, ABBV-CLS-484, that presents a two-pronged strategy for combating cancer. This molecule not only enhances the efficacy of immune cells but also makes tumors more susceptible to immunological intervention, indicating substantial promise for advancements in cancer immunotherapy.
Currently under clinical investigation, this small molecule amplifies the responsiveness of immune cells and heightens the vulnerability of tumors to immune system attacks.
Immunotherapeutic medications known as PD-1 inhibitors are generally employed to activate the immune system in fighting cancer; however, a large fraction of patients either do not react positively to these drugs or eventually develop resistance. The new small-molecule drug candidate, now in its initial clinical trials, aims to heighten the effectiveness of immunotherapies for such patients.
Today (October 4), a study published in the journal Nature has confirmed that this small molecule functions through dual mechanisms to impede tumor growth and prolong survival in laboratory animals.
Scientists from the Tumor Immunotherapy Discovery Engine (TIDE) at the Broad Institute of MIT and Harvard, in partnership with AbbVie and Calico Life Sciences, report that the molecule simultaneously sensitizes tumors to immune system attacks and amplifies the immunological activity against tumors in murine models.
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Mechanistic Insights and Origins
ABBV-CLS-484 operates by inhibiting the proteins PTPN2 and PTPN1, which normally function to deactivate cellular signaling pathways that stimulate immune cells. The research team discovered that suppressing PTPN2/N1 activity transforms immune cells, known as T and NK cells, into more potent eliminators of tumor cells while also making the tumor cells more susceptible to immunological destruction. Inhibition of these proteins also appears to alleviate T-cell exhaustion, a phenomenon believed to contribute to the resistance against cancer immunotherapies.
Distinctively, this molecule’s bifunctional mode of action—targeting both immune cells and tumor cells—sets it apart from other existing cancer immunotherapies, including PD-1 inhibitors. Researchers speculate that this unique attribute could elucidate its standalone efficacy in animal trials, potentially negating the necessity for combinational treatments with other drugs like anti-PD-1 therapy.
The development of ABBV-CLS-484 was instigated after TIDE researchers identified the PTPN2 gene as a promising target for cancer immunotherapy in 2017. AbbVie and Calico are presently examining this molecule and a related molecule in phase 1 clinical trials.
Expert Commentary
According to Robert Manguso, the co-senior author of the study and an associate member at the Broad Institute, this breakthrough provides an unparalleled opportunity to scrutinize immune responses further. The study also involved co-directors of TIDE, Kathleen Yates at the Broad Institute and a cadre of senior researchers and executives from AbbVie and Calico Life Sciences. The collaboration underscores the synergistic potential of academia and industry to expedite scientific progress, specifically translating early-stage biological findings into clinically relevant compounds.
Keeping Cancer at Bay
Foundational experiments dating back to 2017 identified the PTPN2 gene as a crucial player in modulating the responsiveness of melanoma tumors to PD-1 inhibitor treatment. The gene is notably expressed in T cells and has been shown in previous research to contribute to their activation, thereby enhancing their cancer-controlling capabilities. However, pharmaceutical companies have historically faced challenges in developing inhibitors for these phosphatases due to their strong electric charge. Nonetheless, AbbVie’s successful design of a small molecule capable of penetrating cells to inhibit PTPN2 and PTPN1 phosphatases represents a significant scientific milestone.
Results from animal studies reveal that the molecule slows down tumor growth and improves survival rates, indicating its potential as an independent treatment modality. Additionally, the molecule may augment the efficacy of other immunotherapies when used in combination.
Detailed Mechanism of Action Explored
The research, spearheaded by scientists from the Broad Institute, AbbVie, and Calico, elucidated the molecule’s complex mechanism of action. Their findings suggest that the molecule sensitizes tumor cells to specific immune signals and concurrently enhances the activity of cancer-fighting T and NK cells within animal tumors and human blood samples. The molecule also demonstrated a mitigating effect on T-cell exhaustion, enabling T cells to continue functioning effectively, even under challenging conditions like tumors with minimal immune cell infiltration.
Future Directions
Ongoing work by researchers from TIDE, AbbVie, and Calico is directed towards designing the next phase of clinical trials and identifying markers for patient responsiveness to ABBV-CLS-484.
Reference: “PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumor immunity” by Baumgartner CK, Ebrahimi-Nik H, et al., 4 October 2023, Nature.
DOI: 10.1038/s41586-023-06575-7
Support for this research was partially furnished by Calico Life Sciences.
Frequently Asked Questions (FAQs) about cancer immunotherapy
What is ABBV-CLS-484 and who developed it?
ABBV-CLS-484 is a new small-molecule drug candidate aimed at cancer immunotherapy. It was developed through a collaboration between the Tumor Immunotherapy Discovery Engine (TIDE) at the Broad Institute of MIT and Harvard, AbbVie, and Calico Life Sciences.
What makes ABBV-CLS-484 unique in cancer treatment?
The molecule offers a unique dual-action approach that both increases the activity of immune cells and makes tumors more sensitive to immune attack. This dual mechanism distinguishes it from existing cancer immunotherapies like PD-1 inhibitors.
Is ABBV-CLS-484 currently in clinical trials?
Yes, ABBV-CLS-484 is in early-stage clinical trials. The molecule has shown promise in lab animals, slowing tumor growth and increasing survival rates.
What mechanisms does ABBV-CLS-484 employ to fight cancer?
ABBV-CLS-484 works by blocking PTPN2 and PTPN1 proteins, which are known to inhibit the activation of immune cells. By doing so, it turns T and NK cells into more effective tumor killers and makes tumor cells more vulnerable to immune attack.
How does ABBV-CLS-484 compare to PD-1 inhibitors?
PD-1 inhibitors are a current standard in cancer immunotherapy but often face issues like patient non-responsiveness or resistance. ABBV-CLS-484 aims to improve upon this by offering a dual-action mechanism that could be more effective.
When was the PTPN2 gene identified as a promising target?
The PTPN2 gene was identified as a promising cancer immunotherapy target in 2017 by TIDE researchers at the Broad Institute.
What are the expectations for ABBV-CLS-484 in combination with other drugs?
While ABBV-CLS-484 has shown effectiveness on its own in animal models, there is also evidence to suggest that it may work well in combination with existing immunotherapies like anti-PD-1 drugs.
Who were the key researchers involved in the study?
The study was co-led by Robert Manguso, an associate member at the Broad Institute and an assistant professor at Massachusetts General Hospital Center for Cancer Research, along with Kathleen Yates who co-directs TIDE.
What was the role of CRISPR technology in this research?
TIDE uses CRISPR screens among other tools to systematically identify genes like PTPN2 that cancers use to evade immunotherapy.
Was the study published in a peer-reviewed journal?
Yes, the study was published in the peer-reviewed scientific journal Nature on October 4, 2023.
More about cancer immunotherapy
- Nature Journal Publication
- Broad Institute of MIT and Harvard
- AbbVie’s Official Website
- Calico Life Sciences Website
- Information on PD-1 Inhibitors
- Overview of Cancer Immunotherapy
- MIT and Harvard Collaboration
- Massachusetts General Hospital Center for Cancer Research
- CRISPR Technology Explained
5 comments
that’s some serious science right there. blocking two proteins at once? These guys are onto somethin. can’t wait for more studies.
Didn’t think it was possible to have a molecule this potent. honestly, it’s like science fiction is becoming reality. way to go scientists!
Not the first time I’ve heard of dual-action approaches but this one looks like it’s got legs. Exciting times for cancer research, no doubt.
Gotta say, this AbbVie and Calico team seems to be ahead of the curve. PD-1 inhibitors have limitations but looks like this new drug addresses em. Very cool.
Wow, this is a game changer! Finally some real progress in cancer treatment. And that it’s a small molecule makes it even more promising. Just can’t wait to see this in action.