A pan-allelic human SIRPα-blocking antibody, ES004-B5, promotes tumor killing by enhancing macrophage phagocytosis and subsequently inducing an effective T-cell response

Article

Author: Niu, Xiaofeng ; Zhou, Hongping ; Sun, Jun ; Wang, Chunnian ; Sun, Dawei ; Cui, Xue ; Lu, Hongtao ; Gao, Rui ; Lu, Yefeng ; Qiu, Quan ; Guo, Xiaoli ; Jiang, Haixia

AbstractAs a major immune cell type in the tumor microenvironment, tumor-associated macrophages secrete suppressive factors that can inhibit antitumor immunity and promote tumor progression. One approach trying to utilize macrophages for immunotherapy has been to block the CD47-SIRPα axis, which mediates inhibitory signaling, to promote phagocytosis of tumor cells. Many CD47-targeted agents, namely, anti-CD47 antibodies and SIRPα fusion proteins, were associated with a diverse spectrum of toxicities that limit their use in clinical settings. Universal expression of CD47 also leads to a severe “antigen sink” effect of CD47-targeted agents. Given that the CD47 receptor, SIRPα, has a more restricted expression profile and may have CD47-independent functions, targeting SIRPα is considered to have distinct advantages in improving clinical efficacy with a better safety profile. We have developed ES004-B5, a potentially best-in-class pan-allelic human SIRPα-blocking antibody using hybridoma technology. ES004-B5 binds to major human SIRPα variants through a unique epitope with high affinity. By blocking CD47-induced inhibitory “don't-eat-me” signaling, ES004-B5 exerts superior antitumor activity in combination with anti-tumor-associated antigen antibodies in vitro and in vivo. Unlike CD47-targeted agents, ES004-B5 exhibits an excellent safety profile in nonhuman primates. ES004-B5 has potential to be an important backbone for SIRPα-based combination therapy and/or bispecific antibodies, which will likely overcome the limitations of CD47-targeted agents encountered in clinical settings.

01 Jun 2006·Experimental oncology

Antitumor activities of the four sesquiterpene lactones from Elephantopus scaber L.

Article

Author: Xu, G ; Liang, Q ; He, S ; Gong, Z ; Yu, W ; Xi, L

AIMTo evaluate antitumor activity of sesquiterpene lactones (scabertopin (ES-2), isoscabertopin (ES-3), deoxyelephantopin (ES-4), isodeoxyelephantopin (ES-5)) isolated from Elephantopus scaber L. in vitro and in vivo.METHODSSMMC-7721, Caco-2 and HeLa cell lines were treated with ES-2,3,4,5. Cell viability was determined by MTT assay. Agarose gel electrophoresis was used to detect DNA fragmentation. To evaluate in vivo antitumor activity of ES-4, experimental murine tumor model was used.RESULTSIt was shown that ES-2, ES-4, ES-5 exhibited significant antitumor effect in vitro in a concentration-dependent manner. However, the effect of ES-3 on the growth of tested cell lines was relatively weak. In HeLa cells exposed to ES-4 for 48 h, morphological changes and DNA ladder pattern evidencing on apoptosis were detected. ES-4 revealed in vivo antitumor activity.CONCLUSIONAntitumor activity of studied sesquiterpene lactones may be due, at least in part, to induction of apoptosis in vitro. ES-4 possesses also antitumor activity in vivo.

01 Aug 2001·ToxicologyQ3 · MEDICINE

Altered expression of the carboxylesterases ES-4 and ES-10 by peroxisome proliferator chemicals

Q3 · MEDICINE

Article

Author: Michele Poole ; J.Christopher Corton ; Kristie Bridgers ; Stefan E.H. Alexson

The nonspecific carboxylesterases (EC.3.1.1.1) are a large group of enzymes that play important roles in the metabolism of foreign xenobiotics and endogenous lipids, including activators of the peroxisome proliferator-activated receptor alpha, a nuclear receptor that is the central mediator of peroxisome proliferator (PP) effects in the rodent liver. A number of reports have demonstrated that PP exposure leads to alterations in levels of carboxylesterases in the liver. In this study, we determined by Western blot analysis whether exposure to diverse PP results in alteration of expression of two highly expressed microsomal carboxylesterases. Chronic exposure to the PP WY-14,643 (WY) and gemfibrozil (GEM), but not di-n-butyl phthalate (DBP), led to decreases in ES-4 in male rat livers. ES-4 was increased in female rat livers treated with GEM. WY exposure led to decreases in ES-10 in male and female rat livers. ES-10 was increased in female rats treated with DBP. Compared with other end points that are altered within days after PP exposure, the downregulation of ES-4 and ES-10 by WY was considerably slower, occurring between 1 and 5 weeks of exposure. Decreased expression of ES-4 was observed at doses of WY or GEM as low as 10 or 8000 ppm, respectively, whereas decreased expression of ES-10 was more resistant to changes by any PP occurring only with WY at doses as low as 50 ppm. After chronic exposure to WY or diethylhexyl phthalate in wild-type mice, kidney, but not liver, expression of ES-4 and ES-10 was downregulated. These decreases in kidney ES expression were not observed in PPARalpha-null mice lacking a functional PPARalpha gene, demonstrating the importance of this transcription factor in these changes. These studies demonstrate that ES protein expression is under complex control by PP that is sex- and compound-dependent. These results lend support to the hypothesis that PP exposure leads to a reprogramming of expression of enzymes important in the metabolism of PPARalpha activators.

News (Medical) associated with ES-004

21 Oct 2022

·www.biospace.com

Elpiscience Announces Five Poster Presentations at Society for Immunotherapy of Cancer (SITC) 2022 Annual Meeting

SHANGHAI & SUZHOU, China & GERMANTOWN, Md.--(BUSINESS WIRE)-- Elpiscience Biopharma, Inc. (“Elpiscience”), a clinical-stage biopharmaceutical company focused on developing next-generation immunotherapies to benefit cancer patients worldwide, today announced it will have five poster presentations at the SITC 2022 Annual Meeting being held in Boston, Massachusetts from November 8-12. The posters will highlight studies on five innovative molecules including anti-SIRPα monoclonal antibody ES004, anti-LAG3 monoclonal antibody ES005, anti-LILRB2 monoclonal antibody ES009, anti-SIGLEC15 antibody ES012, and PD-L1/SIRPα bispecific macrophage engager ES019. Poster presentations: 1. Title: Treatment of anti-SIRPα in combination with anti-TAA exerts superior anti-tumor activity Abstract No.: 793 Date and time: 11/10/2022, 9:00 am - 9:00 pm (EST) 2. Title: Dual targeting of innate and adaptive immune checkpoints with a PD-L1/SIRPα bispecific macrophage engager to promote anti-tumor activity Abstract No.: 1211 Date and time: 11/10/2022, 9:00 am - 9:00 pm (EST) 3. Title: SIGLEC15 induces monocyte apoptosis and an SIGLEC15 antibody ES012 reverses myeloid cells driven immunosuppression Abstract No.: 1401 Date and time: 11/10/2022, 9:00 am - 9:00 pm (EST) 4. Title: ES005, a high affinity anti-LAG3 monoclonal antibody, inhibits the interactions between LAG3 and multiple ligands and enhances anti-tumor activity of T cells in preclinical models Abstract No.: 426 Date and time: 11/11/2022, 9:00 am - 9:00 pm (EST) 5. Title: ES009, a LILRB2-specific blocking antibody, reprograms myeloid cells into pro-inflammation phenotype and potentiates T cell activation Abstract No.: 1062 Date and time: 11/11/2022, 9:00 am - 9:00 pm (EST) About Elpiscience: Elpiscience is a clinical-stage biopharmaceutical company focused on developing next-generation immunotherapy to benefit cancer patients worldwide. The Company has a robust pipeline of globally innovative cancer immunotherapies covering wide range of oncology targets and multiple proprietary technologies to enable discovery including its Bispecific Macrophage Engager (BiME®) antibody platform for solid tumors. Founded and managed by a team of biotechnology industry leaders and scientists, Elpiscience is supported by a world-class Scientific Advisory Board and high-quality investors including, Lilly Asia Ventures, GL Ventures, Hyfinity Investments, Greater Bay Area Homeland Development Fund, CDH, DYEE Capital and Cormorant Asset Management. To learn more, visit elpiscience.com and follow us on LinkedIn.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	CN	Elpiscience (Suzhou) Biopharma, Ltd.	-

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