Original Study|Articles in Press

Phase 1 Study of Safety and Preliminary Clinical Activity of JNJ-63898081, a PSMA and CD3 Bispecific Antibody, for Metastatic Castration-Resistant Prostate Cancer

Published:February 27, 2023DOI:

      Key Messages

      • JNJ-63898081 (JNJ-081) is a bispecific antibody designed to form an immune synapse between PSMA-expressing tumor cells and CD3-expressing T cells.
      • In this phase 1 study, subcutaneous JNJ-081 was associated with prevalent anti-drug antibody formation.
      • Although dose escalation did not reach its full potential, this study contributed to our understanding of both the safety profile and tumor targeting with an anti-PSMA and CD3 bispecific in patients with metastatic resistant prostate cancer.



      Cancer immunotherapies have limited efficacy in prostate cancer due to the immunosuppressive prostate microenvironment. Prostate specific membrane antigen (PSMA) expression is prevalent in prostate cancer, preserved during malignant transformation, and increases in response to anti-androgen therapies, making it a commonly targeted tumor associated antigen for prostate cancer. JNJ-63898081 (JNJ-081) is a bispecific antibody targeting PSMA-expressing tumor cells and CD3-expressing T cells, aiming to overcome immunosuppression and promoting antitumor activity.

      Patients and Methods

      We conducted a phase 1 dose escalation study of JNJ-081 in patients with metastatic castration-resistance prostate cancer (mCRPC). Eligible patients included those receiving ≥1 prior line treatment with either novel androgen receptor targeted therapy or taxane for mCRPC. Safety, pharmacokinetics, and pharmacodynamics of JNJ-081, and preliminary antitumor response to treatment were evaluated. JNJ-081 was administered initially by intravenous (IV) then by subcutaneous (SC) route.


      Thirty-nine patients in 10 dosing cohorts received JNJ-081 ranging from 0.3 µg/kg to 3.0 µg/kg IV and 3.0 µg/kg to 60 µg/kg SC (with step-up priming used at higher SC doses). All 39 patients experienced ≥1 treatment-emergent AE, and no treatment-related deaths were reported. Dose-limiting toxicities were observed in 4 patients. Cytokine release syndrome (CRS) was observed at higher doses with JNJ-081 IV or SC; however, CRS and infusion-related reaction (IRR) were reduced with SC dosing and step-up priming at higher doses. Treatment doses >30 µg/kg SC led to transient PSA decreases. No radiographic responses were observed. Anti-drug antibody responses were observed in 19 patients receiving JNJ-081 IV or SC.


      JNJ-081 dosing led to transient declines in PSA in patients with mCRPC. CRS and IRR could be partially mitigated by SC dosing, step-up priming, and a combination of both strategies. T cell redirection for prostate cancer is feasible and PSMA is a potential therapeutic target for T cell redirection in prostate cancer.



      ARSI (androgen receptor synthesis inhibitor), CRS (cytokine release syndrome), ECOG PS (European Eastern Cooperative Oncology Group Performance Status), IRR (infusion-related reaction), MABEL (minimum anticipated biological effect level), mCRPC (metastatic castration-resistant prostate cancer), PSMA (prostate-specific membrane antigen), PSA (prostate-specific antigen), PCWG3 (Prostate Cancer Clinical Trials Working Group 3), RECIST (Response Evaluation Criteria in Solid Tumors)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Genitourinary Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Akaza H
        • Procopio G
        • Pripatnanont C
        • et al.
        Metastatic castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy: treatment patterns from the PROXIMA prospective registry.
        J Glob Oncol. 2018; 4: 1-12
        • Facchini G
        • Caffo O
        • Ortega C
        • et al.
        Very early PSA response to abiraterone in mCRPC patients: a novel prognostic factor predicting overall survival.
        Front Pharmacol. 2016; 7: 123
        • Lin TT
        • Chen YH
        • Wu YP
        • et al.
        Risk factors for progression to castration-resistant prostate cancer in metastatic prostate cancer patients.
        J Cancer. 2019; 10: 5608-5613
        • de Wit R
        • de Bono J
        • Sternberg CN
        • et al.
        Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer.
        N Engl J Med. 2019; 381: 2506-2518
        • de Bono J
        • Mateo J
        • Fizazi K
        • et al.
        Olaparib for metastatic castration-resistant prostate cancer.
        N Engl J Med. 2020; 382: 2091-2102
        • Sayegh N
        • Swami U
        • Agarwal N.
        Recent advances in the management of metastatic prostate cancer.
        JCO Oncol Pract. 2022; 18: 45-55
        • Crawford ED
        • Heidenreich A
        • Lawrentschuk N
        • et al.
        Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations.
        Prostate Cancer Prostatic Dis. 2019; 22: 24-38
        • Hansen AR
        • Massard C
        • Ott PA
        • et al.
        Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study.
        Ann Oncol. 2018; 29: 1807-1813
        • Slovin SF
        • Higano CS
        • Hamid O
        • et al.
        Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study.
        Ann Oncol. 2013; 24: 1813-1821
        • Antonarakis ES
        • Piulats JM
        • Gross-Goupil M
        • et al.
        Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study.
        J Clin Oncol. 2020; 38: 395-405
        • Boudadi K
        • Suzman DL
        • Anagnostou V
        • et al.
        Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer.
        Oncotarget. 2018; 9: 28561-28571
        • Stultz J
        • Fong L.
        How to turn up the heat on the cold immune microenvironment of metastatic prostate cancer.
        Prostate Cancer Prostatic Dis. 2021; 24: 697-717
        • Heitmann JS
        • Pfluegler M
        • Jung G
        • Salih HR.
        Bispecific antibodies in prostate cancer therapy: current status and perspectives.
        Cancers (Basel). 2021; : 13
        • Kinoshita Y
        • Kuratsukuri K
        • Landas S
        • et al.
        Expression of prostate-specific membrane antigen in normal and malignant human tissues.
        World J Surg. 2006; 30: 628-636
        • Queisser A
        • Hagedorn SA
        • Braun M
        • Vogel W
        • Duensing S
        • Perner S.
        Comparison of different prostatic markers in lymph node and distant metastases of prostate cancer.
        Mod Pathol. 2015; 28: 138-145
        • Ross JS
        • Sheehan CE
        • Fisher HA
        • et al.
        Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer.
        Clin Cancer Res. 2003; 9: 6357-6362
        • Silver DA
        • Pellicer I
        • Fair WR
        • Heston WD
        • Cordon-Cardo C.
        Prostate-specific membrane antigen expression in normal and malignant human tissues.
        Clin Cancer Res. 1997; 3: 81-85
        • Wright Jr, GL
        • Grob BM
        • Haley C
        • et al.
        Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy.
        Urology. 1996; 48: 326-334
        • Hernandez-Hoyos G
        • Sewell T
        • Bader R
        • et al.
        MOR209/ES414, a novel bispecific antibody targeting PSMA for the treatment of metastatic castration-resistant prostate cancer.
        Mol Cancer Ther. 2016; 15: 2155-2165
        • Klinger M
        • Benjamin J
        • Kischel R
        • Stienen S
        • Zugmaier G.
        Harnessing T cells to fight cancer with BiTE(R) antibody constructs–past developments and future directions.
        Immunol Rev. 2016; 270: 193-208
        • Haber L
        • Olson K
        • Kelly MP
        • et al.
        Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning.
        Sci Rep. 2021; 11: 14397
        • Klinger M
        • Brandl C
        • Zugmaier G
        • et al.
        Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab.
        Blood. 2012; 119: 6226-6233
        • Burt R
        • Warcel D
        • Fielding AK.
        Blinatumomab, a bispecific B-cell and T-cell engaging antibody, in the treatment of B-cell malignancies.
        Hum Vaccin Immunother. 2019; 15: 594-602
        • Budde LE
        • Sehn LH
        • Matasar M
        • et al.
        Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study.
        Lancet Oncol. 2022; 23: 1055-1065
        • Hutchings M
        • Morschhauser F
        • Iacoboni G
        • et al.
        Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-Cell lymphoma: a phase I trial.
        J Clin Oncol. 2021; 39: 1959-1970
        • Moreau P
        • Garfall AL
        • van de Donk N
        • et al.
        Teclistamab in relapsed or refractory multiple myeloma.
        N Engl J Med. 2022; 387: 495-505
        • Verkleij CPM
        • Broekmans MEC
        • van Duin M
        • et al.
        Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma.
        Blood Adv. 2021; 5: 2196-2215
        • Nathan P
        • Hassel JC
        • Rutkowski P
        • et al.
        Overall survival benefit with tebentafusp in metastatic uveal melanoma.
        N Engl J Med. 2021; 385: 1196-1206
        • Beer TM
        • Kwon ED
        • Drake CG
        • et al.
        Randomized, double-blind, Phase III Trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer.
        J Clin Oncol. 2017; 35: 40-47
        • Kwon ED
        • Drake CG
        • Scher HI
        • et al.
        Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.
        Lancet Oncol. 2014; 15: 700-712
        • Hummel HD
        • Kufer P
        • Grullich C
        • et al.
        Pasotuxizumab, a BiTE((R)) immune therapy for castration-resistant prostate cancer: phase I, dose-escalation study findings.
        Immunotherapy. 2021; 13: 125-141
        • Deegen P
        • Thomas O
        • Nolan-Stevaux O
        • et al.
        The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has potent antitumor activity in preclinical models of metastatic castration-resistant prostate cancer.
        Clin Cancer Res. 2021; 27: 2928-2937
        • De Bono JS
        • Fong L
        • Beer TM
        • et al.
        Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC).
        J Clin Oncol. 2021; 39: 5013
      1. Tran B, Horvath L, Rettig M, et al. Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting prostate-specific membrane antigen, in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 38, no. 15_suppl.

        • Yanez JA
        • Remsberg CM
        • Sayre CL
        • Forrest ML
        • Davies NM.
        Flip-flop pharmacokinetics–delivering a reversal of disposition: challenges and opportunities during drug development.
        Ther Deliv. 2011; 2: 643-672
        • Chen X
        • Kamperschroer C
        • Wong G
        • Xuan D.
        A modeling framework to characterize cytokine release upon T-cell-engaging bispecific antibody treatment: methodology and opportunities.
        Clin Transl Sci. 2019; 12: 600-608
        • Lee SC
        • Ma JSY
        • Kim MS
        • et al.
        A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand.
        Sci Adv. 2021; 7: 1-11
        • Jarvi NL
        • Balu-Iyer SV.
        Immunogenicity challenges associated with subcutaneous delivery of therapeutic proteins.
        BioDrugs. 2021; 35: 125-146