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TitleAMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer.
Journal, issue, pagesCancer Discov, Vol. 14, Issue 1, Page 90-9103, Year 2024
Publish dateJan 12, 2024
AuthorsOlivier Nolan-Stevaux / Cong Li / Lingming Liang / Jinghui Zhan / Juan Estrada / Tao Osgood / Fei Li / Hanzhi Zhang / Ryan Case / Christopher M Murawsky / Bram Estes / Gregory L Moore / Matthew J Bernett / Umesh Muchhal / John R Desjarlais / Binnaz K Staley / Jennitte Stevens / Keegan S Cooke / Famke Aeffner / Oliver Thomas / Julia Stieglmaier / Jae-Lyun Lee / Angela Coxon / Julie M Bailis /
PubMed AbstractThe tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We ...The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell-dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo. The avidity-driven activity of AMG 509 enables selectivity for tumor cells with high STEAP1 expression compared with normal cells. AMG 509 is the first STEAP1 TCE to advance to clinical testing, and we report a case study of a patient with mCRPC who achieved an objective response on AMG 509 treatment.
SIGNIFICANCE: Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Kelly et al., p. 76. This article is featured in Selected Articles from This Issue, p. 5.
External linksCancer Discov / PubMed:37861452
MethodsEM (single particle)
Resolution3.0 Å
Structure data

42124

8ucd

EMDB-42124, PDB-8ucd:
Cryo-EM structure of human STEAP1 in complex with AMG 509 Fab
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM / POPC

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM / Flavin adenine dinucleotide

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE / Heme B

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
Keywordsmembrane protein/immune system / membrane protein / antibody / cancer / membrane protein-immune system complex

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