Regression of Human Prostate Cancer Xenografts in Mice by AMG 212/BAY2010112, a Novel PSMA/CD3-Bispecific BiTE Antibody Cross-Reactive with Non-Human Primate Antigens

Friedrich, Matthias; Raum, Tobias; Lutterbuese, Ralf; Voelkel, Markus; Deegen, Petra; Rau, Doris; Kischel, Roman; Hoffmann, Patrick; Brandl, Christian; Schuhmacher, Joachim; Müeller, Peter R.; Finnern, Ricarda; Fuergut, Melanie; Zopf, Dieter; Slootstra, Jerry W.; Baeuerle, Patrick A.; Rattel, Benno; Kufer, Peter

doi:10.1158/1535-7163.mct-12-0042

Cited by 116 publications

(94 citation statements)

References 25 publications

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“…Purification of the monomeric protein was performed in a two-step process using immobilized nickel chelate chromatography followed by size exclusion chromatography, as described for other BiTE antibody constructs. 26,27 Cell lines and cell culture Cell lines were obtained from ATCC and DSMZ. The cells were cultured as described in the supplier's description and tested to exclude mycoplasma contamination.…”

Section: Methodsmentioning

confidence: 99%

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

et al. 2016

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B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ε (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMApositive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/ refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

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Section: Methodsmentioning

confidence: 99%

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

et al. 2016

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“…Neoexpression of CD33 on blinatumomab-activated T cells did not exceed 6% of all T cells even after very long incubation periods. This is in contrast with CD69 or CD25 where typically >50% of all T cells become within short time positive for the activation markers following BiTE stimulation (21,32,33). We therefore do not consider shedding or CD33 neoexpression on a low percentage of activated T cells a particular issue for the efficacy of AMG 330.…”

Section: Discussionmentioning

confidence: 95%

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

Friedrich

Henn

Raum

et al. 2014

Molecular Cancer Therapeutics

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114

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There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell-engaging (BiTE, a registered trademark of Amgen) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3e of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC 50 values ranging between 0.4 pmol/L and 3 pmol/L (18-149 pg/mL) by previously resting, AMG 330-redirected T cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of IFN-g, TNF, interleukin (IL)-2, IL-10, and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of patients with AML did not significantly affect activities of AMG 330. Neoexpression of CD33 on newly activated T cells was negligible as it was limited to 6% of T cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T cells. AMG 330 warrants further development as a potential therapy for AML. Mol Cancer Ther; 13(6); 1549-57. Ó2014 AACR.

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“…MOR209/ES414 was expressed as a recombinant single polypeptide in a CHO cell line and purified from cell culture supernatant using affinity chromatography and size exclusion chromatography. The anti-PSMA Â anti-CD3 scFv-scFv comparator contains the amino acid sequence of BAY2010112 (16,18), and was expressed recombinantly using either transient transfection of HEK293 cells or a CHO cell line. Anti-PSMA Â anti-CD3 scFv-scFv was purified from cell culture supernatant using IMAC affinity chromatography and size exclusion chromatography; no differences were observed between proteins produced in HEK293 or CHO cells.…”

Section: Molecular Biology and Reagent Generationmentioning

confidence: 99%

“…PSMA has been used as a target for the development of diagnostics (10) and for therapeutic mAbs (11)(12)(13)(14). Bispecific antibody fragments in either a diabody format (15) or a tandem singlechain variable fragment (scFv) format (16) targeting PSMA and the T-cell receptor (TCR) complex subunit CD3e have been described previously. One of these molecules, BAY2010112, is currently under early clinical evaluation.…”

Section: Introductionmentioning

confidence: 99%

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

Hernández-Hoyos

Sewell

Bader

et al. 2016

Molecular Cancer Therapeutics

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Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3e to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMAexpressing tumor cells by MOR209/ES414 triggered potent targetdependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID g (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. Ó2016 AACR.

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Regression of Human Prostate Cancer Xenografts in Mice by AMG 212/BAY2010112, a Novel PSMA/CD3-Bispecific BiTE Antibody Cross-Reactive with Non-Human Primate Antigens

Abstract: For treatment of patients with prostate cancer (PCa), we developed a novel T cell-engaging (BiTE) antibody designated AMG 212 or BAY2010112 that is bispecific for prostate-specific membrane antigen (PSMA) and the CD3 epsilon subunit of the T cell receptor complex.

Cited by 116 publications

References 25 publications

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

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

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