Well, the CEO has been abusing shareholders for years. And the recent business plan has been to use the ATM for salaries and research, hell-be-damned.
Nobody was going to stick around for that sort of act.
However! The objective is to turn the corner, and I like three of the new programs. Any hit, and the leverage is enormous.
Won't post tons of old work. But MDSCs are my faves, and I feel that this is not just a wing-it project for complementing PD-1.... catches my eye, will catch many eyes. There is NO first mover advantage to cldx in antibody generation. Anybody can now catch up in two months, just by contracting with the correct group. But cldx seems to be particularly adapt at moving projects through preclinical and into humans. Most recently, the Fc-modified anti-kit. But a bispecific is right behind it, and I am hoping that anti-MerTK is deep into toxicology. Anyway..... maybe Marucci will embrace a traditional business plan, now that he's reloaded.......
Cancer Immunol Res. 2019 Oct;7(10):1672-1686. doi: 10.1158/2326-6066.CIR-19-0008. Epub 2019 Aug 26.
TAM Family Receptor Kinase Inhibition Reverses MDSC-Mediated Suppression and Augments Anti-PD-1 Therapy in Melanoma.
Holtzhausen A1, Harris W1, Ubil E1, Hunter DM1, Zhao J2, Zhang Y2, Zhang D2, Liu Q2, Wang X2, Graham DK3, Frye SV1,2, Earp HS4,5.
1
UNC Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
2
Center for Integrative Chemical Biology and Drug Discovery, Division for Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
3
Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia.
4
UNC Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Shelton_Earp@med.unc.edu.
5
Department of Medicine, Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)>20-fold, polymorphonuclear MDSCs (PMN-MDSC)>15-fold] in tumor-bearing mice. MDSCs from tumor-bearing Mertk-/-, Axl-/- , and Tyro3-/- mice exhibited diminished suppressive enzymatic capabilities, displayed deficits in T-cell suppression, and migrated poorly to tumor-draining lymph nodes. In coimplantation experiments using TYRO3-/-, AXL-/-, and MERTK-/- MDSCs, we showed the absence of these RTKs reversed the protumorigenic properties of MDSCs in vivo Consistent with these findings, in vivo pharmacologic TYRO3, AXL, and MERTK inhibition diminished MDSC suppressive capability, slowed tumor growth, increased CD8+ T-cell infiltration, and augmented anti-PD-1 checkpoint inhibitor immunotherapy. Mechanistically, MERTK regulated MDSC suppression and differentiation in part through regulation of STAT3 serine phosphorylation and nuclear localization. Analysis of metastatic melanoma patients demonstrated an enrichment of circulating MERTK+ and TYRO3+ M-MDSCs, PMN-MDSCs, and early-stage MDSCs (e-MDSC) relative to these MDSC populations in healthy controls. These studies demonstrated that TYRO3, AXL, and MERTK control MDSC functionality and serve as promising pharmacologic targets for regulating MDSC-mediated immune suppression in cancer patients.
(from August, so not that old) |
