Harnessing the immune system to achieve deep and durable clinical responses in cancer
Leveraging our geographically precise solutions (GPS) platform, we are building a pipeline of tumor-selective cytokine and checkpoint inhibitor immunotherapies to treat cancer. Our goal is to overcome the limitations of current immuno-oncology therapies by developing products with an improved efficacy-to-toxicity ratio, or therapeutic index.
We selected molecules that have prior clinical validation demonstrating therapeutic benefit, but are limited by significant toxicities that may be addressed with our approach. Our molecules are engineered to localize activity within the tumor microenvironment without systemic effect, resulting in the potential to achieve enhanced anti-tumor activity.
Tumor-selective anti-CTLA-4 antibody
Tumor-selective anti-CTLA-4 antibody
Updated as of May 12, 2022.
Checkpoint Inhibitor Program
XTX101 is a clinical-stage, tumor-selective anti-CTLA-4 mAb that is designed to improve upon the therapeutic index of existing anti-CTLA-4 therapies. Leveraging our GPS platform, we have engineered XTX101 to enhance the desirable features of an anti-CTLA-4 antibody while addressing its known liabilities.We are currently advancing XTX101 in a Phase 1 clinical trial in patients with solid tumors. Our Phase 1 dose-escalation trial will evaluate XTX101 in the monotherapy and anti-PD-1 combination settings and assess the tolerability of XTX101 at the target dose with the goal of establishing a recommended Phase 2 dose, both as a monotherapy and in combination with pembrolizumab. For more information, please visit clinicaltrials.gov.
In May 2021, we entered into a clinical trial collaboration and supply agreement with Merck, known as MSD outside the United States and Canada, to explore XTX101 in combination with pembrolizumab in patients with solid tumors.
The major focus in our cytokine programs is the development of cytokines with exemplary clinical activity and tolerability. These programs include XTX202, our optimized IL-2 product candidate, and XTX301, our optimized IL-12 product candidate.
XTX202 is a modified form of IL-2 that is masked with a protein domain to prevent binding activity until cleaved off by tumor microenvironment (TME)-associated proteases. The critical challenge in the development of IL-2 therapeutics is to improve patient tolerability without reducing efficacy.Deploying the key structural components of our GPS platform, we have designed XTX202 with key features intended to ensure that XTX202 is released and activated preferentially within the TME, where it has been designed to bind to lymphocytes. In the TME, XTX202 is designed to be unmasked and to bind to the IL-2 βγ receptors that are abundantly expressed on CD8+ T effector cells and NK cells, activating these cells. Locally activated T cells and NK cells have potent anti-tumor cytotoxic activity. The unmasked XTX202 is then rapidly internalized by these lymphocytes, shortening the systemic half-life of the unmasked molecule.
In preclinical studies, we observed that XTX202 was activated in a protease-dependent manner, exhibited tumor growth inhibition and was well-tolerated.
In January 2022, we initiated a Phase 1/2 clinical trial evaluating XTX202 for the treatment of solid tumors. The Phase 1 portion of the trial consists of a dose-escalation monotherapy cohort designed to evaluate the safety and tolerability of XTX202 and determine the recommended Phase 2 dose.
XTX301 is an engineered form of IL-12 that is masked with a protein domain to prevent binding activity until cleaved off by TME-associated proteases. Our goal for our IL-12 program is to create a tumor-selective, extended half-life IL-12 therapeutic with minimal peripheral effects.The design of our masked IL-12 cytokine molecule is closely related to that of our masked IL-2 cytokine molecule, which illustrates the flexibility and robustness of our cytokine engineering approach. The masking domain is designed to prevent binding to cell-surface expressed high affinity IL-12 receptor, unless the linker containing the protease site is cleaved by proteases preferentially active in the TME. The half-life extension domain is designed to overcome the short circulating half-life of the native cytokine and the overall molecule is designed to enhance the efficiency of manufacturing.
In preclinical studies, we observed that XTX301 was activated in a protease-dependent manner and was clinically active and well-tolerated. We are currently advancing XTX301 through IND-enabling studies, and we plan to evaluate XTX301 as a monotherapy and combination agent for the treatment of solid tumors.