Xaluritamig (AMG-509) is a bispecific T cell engager and cytolytic agent with a K d of 27.6 nM for human CD3ε. Xaluritamig binds to CD3ε via an anti- CD3 single-chain variable fragment ( scFv ) domain, and to STEAP1 via a bispecific anti- STEAP1 antigen-binding fragment (Fab) domain, thereby recruiting and activating T cells and forming a bridge between T cells and STEAP1 -expressing cancer cells. Xaluritamig induces T cell-mediated redirected cytotoxicity, tumor cell lysis, cytokine release, CD8 + T cell activation and expansion, as well as tumor stasis or regression. Xaluritamig contains an Fc domain with no effector function, which prolongs serum half-life, exhibits only minimal activity against cells with low STEAP1 expression and normal cells, and shows extremely low target-related off-tumor toxicity in cynomolgus monkeys. Xaluritamig is used in STEAP1×CD3 XmAb 2+1 immunotherapy and in research on metastatic castration-resistant prostate cancer and Ewing sarcoma [1] [2] [3].
In Vivo, Xaluritamig (0.01-1 mg/kg; intravenous injection; twice at an interval of 7 days; total duration of 16 days) induces significant antitumor activity in the NSG mouse subcutaneous xenograft model of 22Rv1-LucSTEAP1, with the 0.01 mg/kg dose group achieving 99.7% tumor growth inhibition (complete tumor stasis)[4]. Xaluritamig (0.3 mg/kg; intravenous injection; administered twice at a 7-day interval; total duration of 17 days) significantly inhibits tumor growth in the tibial bone metastasis model of Myc-CaP-LucSTEAP1 in FVB/N huCD3ε knock-in mice, but its combination with anti-PD-1 antibody does not enhance anti-tumor activity[4]. Xaluritamig (10 μg/kg, or an additional 40 μg/kg; intravenous injection; for 28 consecutive days) is well tolerated in male and female Mauritian-origin cynomolgus monkeys. Serum exposure is nearly dose-proportional, with no serious target-related off-tumor toxicity[4].
In Vitro, Xaluritamig (AMG-509) binds specifically to 293T cells transfected with human STEAP1, with an EC50 of 3.8 nM[2]. Xaluritamig potently induces T cell-mediated lysis of STEAP1-positive human cancer cells, with a median EC50 of 37 pM across 19 cell lines; it shows no activity against STEAP1-knockout prostate cancer cells[2].\n Xaluritamig redirects prostate cancer cell lysis with higher potency than the anti-STEAP1 Fab XmAb molecule alone; it preferentially kills cancer cells with high STEAP1 expression and exhibits extremely low activity against normal cells[2]. Xaluritamig induces only extremely low levels of cytotoxicity in STEAP1-low-expressing human normal bronchial smooth muscle cells and aortic endothelial cells cultured in vitro[3].
References:
[1]. Kelly WK, et al. Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study. Cancer Discov. 2024 Jan 12;14(1):76-89.
[2]. Li C, et al. 718 AMG 509, a STEAP1 x CD3 bispecific XmAb® 2+ 1 immune therapy, exhibits avidity-driven binding and preferential killing of high STEAP1-expressing prostate and Ewing sarcoma cancer cells[J]. 2020.
[3]. Raychaudhuri R, et al. Xaluritamig: A first step towards a new target, new mechanism for metastatic prostate cancer[J]. AME Clinical Trials Review, 2024, 2: 44.
[4]. Nolan-Stevaux O, et al. AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer. Cancer Discov. 2024 Jan 12;14(1):90-103.
In Vivo, Xaluritamig (0.01-1 mg/kg; intravenous injection; twice at an interval of 7 days; total duration of 16 days) induces significant antitumor activity in the NSG mouse subcutaneous xenograft model of 22Rv1-LucSTEAP1, with the 0.01 mg/kg dose group achieving 99.7% tumor growth inhibition (complete tumor stasis)[4]. Xaluritamig (0.3 mg/kg; intravenous injection; administered twice at a 7-day interval; total duration of 17 days) significantly inhibits tumor growth in the tibial bone metastasis model of Myc-CaP-LucSTEAP1 in FVB/N huCD3ε knock-in mice, but its combination with anti-PD-1 antibody does not enhance anti-tumor activity[4]. Xaluritamig (10 μg/kg, or an additional 40 μg/kg; intravenous injection; for 28 consecutive days) is well tolerated in male and female Mauritian-origin cynomolgus monkeys. Serum exposure is nearly dose-proportional, with no serious target-related off-tumor toxicity[4].
In Vitro, Xaluritamig (AMG-509) binds specifically to 293T cells transfected with human STEAP1, with an EC50 of 3.8 nM[2]. Xaluritamig potently induces T cell-mediated lysis of STEAP1-positive human cancer cells, with a median EC50 of 37 pM across 19 cell lines; it shows no activity against STEAP1-knockout prostate cancer cells[2].\n Xaluritamig redirects prostate cancer cell lysis with higher potency than the anti-STEAP1 Fab XmAb molecule alone; it preferentially kills cancer cells with high STEAP1 expression and exhibits extremely low activity against normal cells[2]. Xaluritamig induces only extremely low levels of cytotoxicity in STEAP1-low-expressing human normal bronchial smooth muscle cells and aortic endothelial cells cultured in vitro[3].
References:
[1]. Kelly WK, et al. Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study. Cancer Discov. 2024 Jan 12;14(1):76-89.
[2]. Li C, et al. 718 AMG 509, a STEAP1 x CD3 bispecific XmAb® 2+ 1 immune therapy, exhibits avidity-driven binding and preferential killing of high STEAP1-expressing prostate and Ewing sarcoma cancer cells[J]. 2020.
[3]. Raychaudhuri R, et al. Xaluritamig: A first step towards a new target, new mechanism for metastatic prostate cancer[J]. AME Clinical Trials Review, 2024, 2: 44.
[4]. Nolan-Stevaux O, et al. AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer. Cancer Discov. 2024 Jan 12;14(1):90-103.