Sriram Jakkaraju
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Sriram Jakkaraju has a total of 20 co-authors. Here are the top co-authors by number of shared publications:
- Aarron Willingham
Discovery Biologics, Merck & Co., Inc., Rahway, NJ 07065, USA
1 shared publication - An Chi
Chemical Biology, Merck, Boston, MA, USA
1 shared publication - Anirudh Chirala
Discovery Immunology, Merck & Co., Inc., Rahway, NJ 07065, USA
1 shared publication - Arjun Baghela
Data, AI and Genome Sciences, Merck & Co., Inc., Rahway, NJ 07065, USA
1 shared publication - Elisabeth H. Vollmann
Discovery Immunology, Merck & Co., Inc., Rahway, NJ 07065, USA
1 shared publication - Grace Pham Mortenson
Discovery Biologics, Merck & Co., Inc., Rahway, NJ 07065, USA
1 shared publication
Latest Publications
- Open Access
uPAR-Targeting Cytotoxic Antibody–Drug Conjugates Selectively Deplete Proinflammatory Myeloid Cells for Autoimmune Indications
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial inflammation and progressive joint destruction. There is no cure, and patient responses to current therapies vary, reflecting underlying pathogenic heterogeneity. Leveraging single-cell RNA sequencing (scRNA-seq) of RA synovium, we identified a PLAUR/uPAR-high myeloid subset that co-expresses pathogenic mediators, including IL1B and CXCL8. To target these cells, we developed anti-uPAR antibody–drug conjugates (ADCs) and evaluated various payloads in vitro and in vivo. ADCs bearing BCL-2 family inhibitors selectively induced apoptosis in proinflammatory human monocytes and macrophages with elevated uPAR, while sparing unstimulated monocytes with low basal uPAR in vitro. The treatment also reduced CXCL8 secretion. Given that murine myeloid cells exhibited lower uPAR expression and reduced sensitivity to BCL-2 family inhibitors, we used a monomethyl auristatin F (MMAF) payload to demonstrate in vivo proof-of-concept. In an air-pouch model, the anti-uPAR–MMAF conjugate reduced uPARhighCD11b+F4/80+ macrophages by 39% compared with the isotype control. Together, our study underscores the potential of ADCs to eliminate disease-relevant cell types with inducible cell surface markers. This work opens new avenues for exploring cytotoxic ADCs as targeted therapies for autoimmune and inflammatory diseases.
Open AccessuPAR-Targeting Cytotoxic Antibody–Drug Conjugates Selectively Deplete Proinflammatory Myeloid Cells for Autoimmune Indications
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial inflammation and progressive joint destruction. There is no cure, and patient responses to current therapies vary, reflecting underlying pathogenic heterogeneity. Leveraging single-cell RNA sequencing (scRNA-seq) of RA synovium, we identified a PLAUR/uPAR-high myeloid subset that co-expresses pathogenic mediators, including IL1B and CXCL8. To target these cells, we developed anti-uPAR antibody–drug conjugates (ADCs) and evaluated various payloads in vitro and in vivo. ADCs bearing BCL-2 family inhibitors selectively induced apoptosis in proinflammatory human monocytes and macrophages with elevated uPAR, while sparing unstimulated monocytes with low basal uPAR in vitro. The treatment also reduced CXCL8 secretion. Given that murine myeloid cells exhibited lower uPAR expression and reduced sensitivity to BCL-2 family inhibitors, we used a monomethyl auristatin F (MMAF) payload to demonstrate in vivo proof-of-concept. In an air-pouch model, the anti-uPAR–MMAF conjugate reduced uPARhighCD11b+F4/80+ macrophages by 39% compared with the isotype control. Together, our study underscores the potential of ADCs to eliminate disease-relevant cell types with inducible cell surface markers. This work opens new avenues for exploring cytotoxic ADCs as targeted therapies for autoimmune and inflammatory diseases.