MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Hernández-Hoyos, Gabriela; Sewell, Toddy; Bader, Robert; Bannink, Jeannette; Chenault, Ruth A.; Daugherty, Mollie; Dasovich, Maria; Fang, Hang; Gottschalk, Rebecca; Kumer, John; Miller, Robert E.; Ravikumar, Padma; Wiens, Jennifer; Algate, Paul A.; Bienvenue, David; McMahan, Catherine J.; Natarajan, Sateesh K.; Gross, Jane A.; Blankenship, John W.

doi:10.1158/1535-7163.mct-15-0242

Cited by 61 publications

(38 citation statements)

References 24 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of T-cells leads to transient release of cytokines, which engages other immune cells and broadens the immune response against the tumor tissue leading to conversion of a noninflamed (cold) to an inflamed (hot) tumor environment, infiltration and proliferation of T-cells, and serial killing of tumor cells (10)(11)(12)(13). After recent clinical successes of bispecific T-cell engagers with a short half-life (BiTE) for the treatment of hematologic malignancies (14,15), the next generation of T-cell engagers incorporating half-life extension for increased dosing convenience for patients for the treatment of solid tumors is emerging (13,(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

Hipp

Voynov

Drobits-Handl

et al. 2020

Clinical Cancer Research

View full text Add to dashboard Cite

Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues. Experimental Design: The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3 þ T-cells. Results: Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3. Conclusions: This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.

show abstract

Section: Introductionmentioning

confidence: 99%

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

Hipp

Voynov

Drobits-Handl

et al. 2020

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…The bispecific antibody was generated by fusing the scFv of J591, a clinical stage deimmunized mAb targeting PSMA, and the scFv of the clinically approved anti-CD3 OKT-3 antibody (20,22,23). Like other similar studies testing anti-PSMA/CD3 bispecific antibodies (34)(35)(36), the ability of BiJ591 to bind both PSMA and CD3, and also to induce a PSMA-specific cytotoxicity in vitro was demonstrated. In vivo, the short halflife and the therapeutic effect of this bispecific antibody on PSMA-positive PCa xenografts have been confirmed after daily intravenous injection.…”

Section: Discussionmentioning

confidence: 99%

Anti-PSMA/CD3 Bispecific Antibody Delivery and Antitumor Activity Using a Polymeric Depot Formulation

Leconet

Liu

Guo

et al. 2018

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Small therapeutic proteins represent a promising novel approach to treat cancer. Nevertheless, their clinical application is often adversely impacted by their short plasma half-life. Controlled long-term delivery of small biologicals has become a challenge because of their hydrophilic properties and in some cases their limited stability. Here, an forming depot-injectable polymeric system was used to deliver BiJ591, a bispecific T-cell engager (BiTE) targeting both prostate-specific membrane antigen (PSMA) and the CD3 T-cell receptor in prostate cancer. BiJ591 induced T-cell activation, prostate cancer-directed cell lysis, and tumor growth inhibition. The use of diblock (DB) and triblock (TB) biodegradable polyethylene glycol-poly(lactic acid; PEG-PLA) copolymers solubilized in tripropionin, a small-chain triglyceride, allowed maintenance of BiJ591 stability and functionality in the formed depot and controlled its release. In mice, after a single subcutaneous injection, one of the polymeric candidates, TB1/DB4, provided the most sustained release of BiJ591 for up to 21 days. Moreover, the use of BiJ591-TB1/DB4 formulation in prostate cancer xenograft models showed significant therapeutic activity in both low and high PSMA-expressing tumors, whereas daily intravenous administration of BiJ591 was less efficient. Collectively, these data provide new insights into the development of controlled delivery of small therapeutic proteins in cancer..

show abstract

“…In murine xenograft models, MOR209/ES414 also showed significant inhibitory effect on tumor and prolonged the survival time. The half-life period of MOR209/ES414 was 4 days in the peripheral blood of NOD/SCIDγ (NSG) mice [ 149 ]. A phase I study (NCT02262910) of MOR209/ES414 in patients with mCRPC is ongoing.…”

Section: Targeting Antigensmentioning

confidence: 99%

Recent advances of bispecific antibodies in solid tumors

Liu

et al. 2017

J Hematol Oncol

120

View full text Add to dashboard Cite

Cancer immunotherapy is the most exciting advancement in cancer therapy. Similar to immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T), bispecific antibody (BsAb) is attracting more and more attention as a novel strategy of antitumor immunotherapy. BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators. In recent decades, a variety of BsAb formats have been generated. According to the structure of Fc domain, BsAb can be classified into two types: IgG-like format and Fc-free format. Among these formats, bispecific T cell engagers (BiTEs) and triomabs are commonly investigated. BsAb has achieved an exciting breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. In this review, we focus on the preclinical experiments and clinical studies of epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor (HER) family, carcinoembryonic antigen (CEA), and prostate-specific membrane antigen (PSMA) related BsAbs in solid tumors, as well as discuss the challenges and corresponding approaches in clinical application.

show abstract

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Cited by 61 publications

References 24 publications

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

Anti-PSMA/CD3 Bispecific Antibody Delivery and Antitumor Activity Using a Polymeric Depot Formulation

Recent advances of bispecific antibodies in solid tumors

Contact Info

Product

Resources

About