Background: CD19 is a lineage-restricted surface antigen expressed on nearly all stages of B-cell development, making it a pivotal target for immune-directed therapy in B-cell malignancies and autoantibody-mediated diseases. Over the past decade, CD19-directed immune therapies—including chimeric antigen receptor (CAR) T cells, bispecific antibodies, monoclonal antibodies, and antibody–drug conjugates—have transformed hematologic oncology and are now extending into autoimmune disorders. Objective: To systematically review clinical outcomes of CD19-targeted immune therapies across malignant and autoimmune B-cell diseases following PRISMA 2020 guidelines. Methods: PubMed, Embase, Web of Science, and ClinicalTrials.gov were searched (January 2010–October 2025). Randomized controlled trials (RCTs), phase II/III studies, and pivotal single-arm trials were included. Data were appraised using Cochrane RoB 2 and ROBINS-I. Results: CD19-directed CAR-T therapies (axi-cel, liso-cel, tisa-cel, brexu-cel) produced high overall response rates and complete response rates in relapsed/refractory large B-cell lymphoma (LBCL), [1,2]. Blinatumomab improved survival and Measurable residual disease (MRD) clearance in newly diagnosed and relapsed B-cell acute lymphoma leukemia (ALL) [3,4,12,13], and early American College of Rheumatology (ACR) 2025 data suggest efficacy in systemic sclerosis [14]. Blinatumomab also led to compete restoration of platelet counts in a patient with refractory immune thrombocytopenia and antiphospholipid syndrome [17]. Tafasitamab–lenalidomide and loncastuximab tesirine achieved durable responses in diffuse large B cell lymphoma (DLBCL) [5,6]. In autoimmunity, CD19 CAR-T therapy induced drug-free remission in systemic lupus erythematodes (SLE) [7]. Conclusions: CD19 has the potential to become a unifying therapeutic target across hematology and immunology. This approach unifies the treatment of many different diseases by one concept. The indication would include all CD 19 positive B cell diseases.

PDF file - 83KB, Supplementary Figure S1. Characteristics of purified AMG 330.

Figure S5. AMG 160 engages NHP PSMA and CD3 in vitro.

Figure S1. AMG 160 has high binding affinity.

Abstract T cell engager (TCE) molecules are a targeted immune therapy that redirect a patient’s T cells to kill tumor cells. While several TCE molecules have now advanced to approval, clinical development has been challenging, especially in the solid tumor setting. There are few solid tumor surface antigens that are tumor-specific, and antigens with even low levels of expression in normal tissue can be recognized by a TCE and result in on-target off-tumor toxicity. To overcome this challenge, we have developed AMG 305, a first-in-class, dual targeting BiTE® (bispecific T cell engager) molecule that requires binding to both P-cadherin (CDH3) and mesothelin (MSLN) for potent cytotoxic activity. Immunohistochemistry analysis shows that CDH3 and MSLN are co-expressed in multiple solid tumor types. In normal tissues, immunostaining shows fewer tissues have overlapping co-expression than expression of just one or the other target. AMG 305 relies on an avidity-based approach to engage T cells to preferentially kill CDH3+MSLN+ tumor cells, with limited activity against normal cells that express only one of the target antigens. In vitro, AMG 305 induces potent cytotoxicity against tumor cells co-expressing CDH3 and MSLN, with greatly attenuated activity against cells expressing only CDH3 or MSLN. In vivo, AMG 305 demonstrates dose-dependent antitumor activity in a CDH3+MSLN+ xenograft tumor model. AMG 305 was clinically well-tolerated in a nonclinical safety study in cynomolgus monkey. Data from IND-enabling preclinical studies support initiation of the first-in-human study of AMG 305 in CDH3+MSLN+ solid tumors in 2023. Citation Format: Elizabeth Pham, Petra Lutterbuese, Petra Deegen, Natalie Mariano, Katja Matthes, Joachim Wahl, Pamela Bogner, Joan Lane, Kristin Lewis Wilson, Rodolfo Yabut, Virginie Naegele, Ines Ullrich, Stephanie Everts, Markus Muenz, Thomas Boehm, Sabine Stienen, Angela Coxon, Peter Kufer, Tobias Raum, Julie M. Bailis. AMG 305, a dual targeting BiTE®molecule with selective activity for solid tumors that co-express CDH3 and MSLN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND06.

Supplementary Video 4C and D from Selective Targeting and Potent Control of Tumor Growth Using an EphA2/CD3-Bispecific Single-Chain Antibody Construct

Figure S2. Enzalutamide increases PSMA expression levels and may enhance AMG 160-dependent cytotoxicity.

Supplementary Video 4I from Selective Targeting and Potent Control of Tumor Growth Using an EphA2/CD3-Bispecific Single-Chain Antibody Construct

Figure S4. Faster clearance of AMG 160 in the NSG B2M mouse strain.

Supplementary methods, tables, and references.

Figure S3. PSMA-11 does not compete with AMG 160 for PSMA binding.

Analysis of solely bone marrow aspirates

AMG 794 is a half-life extended BiTE® immune therapy targeting the oncofetal antigen Claudin 6 (CLDN6). AMG 794 redirects T cells to kill CLDN6-expressing tumor cells and is being developed for the treatment of non-small cell lung cancer (NSCLC) and epithelial ovarian cancer (EOC). CLDN6 is a compelling tumor antigen that is expressed during embryonic and fetal development, transcriptionally silenced in adult tissues, and re-expressed on the surface of NSCLC and EOC cells. By immunohistochemistry, CLDN6 staining of the cell membrane was observed in 27% of non-squamous NSCLC (n = 63) and 69% of EOC (n = 92) samples, the majority of which were of the high-grade serous ovarian cancer subtype. Expression of CLDN6 protein was not detected in most normal adult tissues, with rare CLDN6 immunostaining limited to individual cells in the pituitary, pancreas, small intestine, kidney, and female reproductive organs. AMG 794 is a fully human BiTE® molecule that binds both human and cynomolgus monkey CLDN6 and CD3. AMG 794 binds human CLDN6 and CD3 with equilibrium dissociation constant (KD) of 13 nM and 36 nM, respectively. In vitro, AMG 794 redirects human T cells to kill CLDN6-expressing cancer cells with a half-maximal lysis concentration (EC50) of 2.6 ± 1.1 pM to 127.4 ± 53.4 pM. Consistent with the mechanism of action of BiTE® immune therapy, AMG 794 induces T cell activation and transient production of cytokines in co-cultures of T cells and CLDN6-expressing tumor cells. Remarkably, AMG 794 binding and cytotoxic activity is selective for CLDN6 over other claudin family proteins, despite high homology in the extracellular loops with CLDN9. Weekly dosing of AMG 794 significantly inhibited the growth of established lung and ovarian xenograft tumors in immunocompromised mice injected with human T cells. Anti-tumor activity was associated with an increase in tumor-infiltrating T cells. AMG 794 was well tolerated in a one-month repeat-dose toxicology study in cynomolgus monkey, with evidence for target engagement. The potent, selective activity of AMG 794 for CLDN6-expressing NSCLC and EOC cells, together with an acceptable nonclinical safety profile, supported the advancement of AMG 794 into clinical development. A first-in-human study to explore the safety, tolerability, pharmacokinetics, and anti-tumor activity of AMG 794 in patients with CLDN6-positive advanced/metastatic non-squamous NSCLC or EOC will be enrolling patients in March 2022. Citation Format: Elizabeth Pham, Anja Henn, Beate Sable, Joachim Wahl, Kip Conner, Katja Matthes, Shivani Gupta, Rodolfo Yabut, Famke Aeffner, Kristin Lewis Wilson, Jonas Anlahr, Christoph Dahlhoff, Vijay Kale, Matthias Friedrich, Tobias Raum, Peter Kufer, Angela Coxon, Sabine Stienen, Julie M. Bailis. AMG 794, a Claudin 6-targeted half-life extended (HLE) bispecific T cell engager (BITE®) molecule for non-small cell lung cancer and epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5202.

Blinatumomab is a first-in-class immunotherapy based on the bispecific T-cell engager (BiTE (R)) immune-oncology platform, which redirects CD3(+) T cells to kill CD19(+) target cells. The objective of this analysis was to describe the correlation between B-and T-cell kinetics and response to blinatumomab in patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL). The clinical efficacy of treatment with blinatumomab in patients with r/r NHL was recently investigated in a phase 1 dose-escalation and expansion trial (NCT00274742) wherein 76 patients received blinatumomab by continuous intravenous infusion at various doses (0.5-90 mu g/m(2)/day). B-Cell depletion and expansion of CD3(+), CD4(+), and CD8(+) T cells was analyzed in patients stratified per clinical response (complete response [CR], n = 16; partial response [PR], stable disease [SD], or progressive disease [PD], n = 54) for at least 4 weeks (additional 4 weeks after clinical benefit) from the date of administration of blinatumomab until dose-limiting toxicity or PD. B-cell depletion kinetics were faster in patients who had a CR than in patients who did not have a complete response (PR, SD, or PD). T-cell expansion (T-cell counts exceeding the baseline level on day 22) was more pronounced in patients with CR than in patients without CR. T-cell expansion in patients with CR correlated with increased T-cell counts of both CD4(+) and CD8(+) T cells compared with patients without CR. Patients with r/r NHL who achieved a CR had faster B-cell depletion and increased expansion of CD3(+), CD4(+), and CD8(+) T cells than patients who did not achieve a CR. (C) 2021 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

Abstract Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy. Experimental Design: We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated in vitro and in mCRPC xenograft models. AMG 160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated. Results: AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines in vitro, with half-maximal lysis of 6–42 pmol/L. In vivo, AMG 160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68–labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs. Conclusions: The preclinical characterization of AMG 160 highlights its potent antitumor activity in vitro and in vivo, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC. See related commentary by Kamat et al., p. 2675

Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE (R)) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 mu g/d; cIV: n = 16, 5-80 mu g/d). The SC maximum tolerated dose was 172.0 mu g/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration:NCT01723475 (ClinicalTrials.gov)

Immuno-oncology therapies engage the immune system to treat cancer. BiTE (bispecific T-cell engager) technology is a targeted immuno-oncology platform that connects patients' own T cells to malignant cells. The modular nature of BiTE technology facilitates the generation of molecules against tumor-specific antigens, allowing off-the-shelf immuno-oncotherapy. Blinatumomab was the first approved canonical BiTE molecule and targets CD19 surface antigens on B cells, making blinatumomab largely independent of genetic alterations or intracellular escape mechanisms. Additional BiTE molecules in development target other hematologic malignancies (eg, multiple myeloma, acute myeloid leukemia, and B-cell non-Hodgkin lymphoma) and solid tumors (eg, prostate cancer, glioblastoma, gastric cancer, and small-cell lung cancer). BiTE molecules with an extended half-life relative to the canonical BiTE molecules are also being developed. Advances in immuno-oncology made with BiTE technology could substantially improve the treatment of hematologic and solid tumors and offer enhanced activity in combination with other treatments.

Abstract Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell–independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell–dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) T-cell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells in vitro, and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells in vitro and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies. Significance: This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.

5034 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is a promising therapeutic target in mCRPC, and pasotuxizumab is a PSMA x CD3 BiTE that mediates tumor cell killing. Methods: NCT01723475 was a first-in-human, multicenter, dose-escalation study in patients (pts) with mCRPC refractory to standard therapy. Pts received pasotuxizumab as a continuous intravenous infusion in cohorts of 3–4 pts. Dose-escalation followed a continuous reassessment methodology design. The primary objective was to determine safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, biomarkers, and tumor response. Results: 16 pts were enrolled into 5 dosing cohorts (5 µg/d, n = 3; 10 µg/d, n = 4; 20 µg/d, n = 3; 40 µg/d, n = 4; 80 µg/d, n = 2). All pts had ≥1 AE of any grade; most common were fever (94%), chills (69%), and fatigue (50%). 13 pts (81%) had ≥1 AE of grade ≥3; most common were decreased lymphocytes and infections (both 44%). No grade 5 AE occurred. A serious AE related to study drug was reported for 1 pt (fatigue, 20 µg/d). No anti-drug antibodies were observed. Recruitment was stopped before MTD was reached to facilitate initiation of a new study sponsored by Amgen. Antitumor activity as indicated by PSA serum level decline was dose dependent, with a mean best PSA change per dosing cohort versus baseline of +0.74% (5 µg/d), –17.9% (10 µg/d), –37.4% (20 µg/d), –42.5% (40 µg/d) and –54.9% (80 µg/d). PSA decreases of ≥50% occurred in 3 pts (n = 1 each in 20 µg/d, 40 µg/d, and 80 µg/d cohorts). One long-term PSA responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter pt showed a complete regression of soft-tissue metastases and marked regression of bone metastases as assessed by PSMA-PET/CT, > 90% reduction in PSA and alkaline phosphatase, and a significant and durable improvement in disease related symptoms. Conclusions: Pasotuxizumab had an acceptable safety profile and dose-dependent clinical activity in mCRPC pts. There were two long term responders in the dose escalation. This is the first clinical study showing that a BiTE immunotherapy can be efficacious in solid tumors. Clinical trial information: NCT01723475.

Immuno‐oncology therapies engage the immune system to treat cancer. BiTE (bispecific T‐cell engager) technology is a targeted immuno‐oncology platform that connects patients' own T cells to malignant cells. The modular nature of BiTE technology facilitates the generation of molecules against tumor‐specific antigens, allowing off‐the‐shelf immuno‐oncotherapy. Blinatumomab was the first approved canonical BiTE molecule and targets CD19 surface antigens on B cells, making blinatumomab largely independent of genetic alterations or intracellular escape mechanisms. Additional BiTE molecules in development target other hematologic malignancies (eg, multiple myeloma, acute myeloid leukemia, and B‐cell non‐Hodgkin lymphoma) and solid tumors (eg, prostate cancer, glioblastoma, gastric cancer, and small‐cell lung cancer). BiTE molecules with an extended half‐life relative to the canonical BiTE molecules are also being developed. Advances in immuno‐oncology made with BiTE technology could substantially improve the treatment of hematologic and solid tumors and offer enhanced activity in combination with other treatments.