Abstract Background: Fibrotic tumors pose a major therapeutic challenge due to the dense stromal barriers formed by myofibroblastic cancer-associated fibroblasts (myCAFs), which increase tissue stiffness and impede drug delivery. These myCAFs are characterized by elevated expression of type XI collagen, a key component of the fibrous cap. Antibody-drug conjugates (ADCs) offer a targeted approach by linking monoclonal antibodies to cytotoxic payloads, enabling selective delivery within the tumor microenvironment. Here, we present a novel ADC-based strategy that targets tumor-associated type XI collagen to selectively eliminate myCAFs. This approach combines CT11a1, an antibody recognizing a tumor-specific type XI collagen epitope, as the delivery vehicle, with PRO-C11, a circulating biomarker of type XI collagen for potential patient selection and treatment monitoring. Methods: ELISAs were used to quantify CT11a1 and PRO-C11 collagen epitopes in serum from patients with various cancer types and healthy controls. Pancreatic cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and co-cultures of CAFs with pancreatic cancer cells (BxPC3) were cultured in the SiaJ model for 12 days. On day 12, cultures were immunostained with CT11a1 or PRO-C11 antibodies. A CT11a1-ADC was developed and its effect on cell viability was quantified using the Alamar Blue assay. Results: Among several tested collagen-based biomarkers, PRO-C11 demonstrated the highest diagnostic accuracy (AUC: 0.99) across all cancer types. In contrast CT11a1 was barely detectable in serum. Immunostaining with the CT11a1 antibody on day 12 of the SiaJ model revealed prominent type XI collagen deposition in wells containing CAFs while minimal to no signal was detected in wells with NFs. In contrast, staining CAFs with the PRO-C11 antibody did not result in any detectable signal, indicating limited accessibility or absence of the PRO-C11 epitope in the extracellular matrix (ECM). Staining of co-cultures with the CT11a1 antibody revealed that type XI collagen is localized in the fibrous cap-like structure positioned between the cancer cells and the fibroblasts. Initial treatments with CT11a1-ADC induced a dose-dependent decrease in CAF viability. Conclusion: Type XI collagen is specific to myCAFs. The CT11a1 epitope is detectable in the CAF-derived ECM, but not in circulation, whereas the opposite is true for PRO-C11. The developed CT11a1-ADC demonstrates potential as an ADC specifically targeting type XI collagen produced by myCAFs. PRO-C11 may serve as a biomarker to identify patients with high type XI collagen production. Further exploration and validation are ongoing. Citation Format: Annika Hettich, Cecilie Bager, Morten Karsdal, Nicholas Willumsen, . Targeting type XI collagen to facilitate elimination of cancer-associated fibroblasts abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5841.
Hettich et al. (Fri,) studied this question.