HER2-specific immunoligands engaging NKp30 or NKp80 trigger NK-cell-mediated lysis of tumor cells and enhance antibody-dependent cell-mediated cytotoxicity

Peipp, Matthias; Derer, Stefanie; Lohse, Stefan; Staudinger, Matthias; Klausz, Katja; Valerius, Thomas; Gramatzki, Martin; Kellner, Christian

doi:10.18632/oncotarget.5135

Cited by 29 publications

(34 citation statements)

References 49 publications

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“…This is especially vital for several therapeutic concepts that involve targeting of different cell types at the same time, such as effector cell redirection. [35][36][37] Similar to Baty and coworkers, 18 we were able to show that the overall architecture of this platform clearly allows for effector cell recruitment enabling tumor cell killing.…”

Section: Namesupporting

confidence: 79%

Biophysical and biochemical characterization of a VHH-based IgG-like bi- and trispecific antibody platform

Pekar

Busch

Valldorf

et al. 2020

mAbs

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Here, we report the characterization of a VHH-derived IgG-like bi-and trispecific antibody platform that essentially relies on the replacement of the VH and VL regions of a conventional antibody by two independently functioning VHH domains. Consequently, a VHH is engrafted onto constant region CH1 while the other VHH-based paratope is engrafted on the constant region of the light chain, Cκ or Cλ, resulting in a tetravalent bispecific IgG-like molecule. Combined with a heavy chain heterodimerization technique, this platform allows facile engineering of bi-and trispecific antibodies with flexible valencies. We demonstrate the general applicability of this generic platform approach and elaborate on the limitations of specific formats.

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Section: Namesupporting

confidence: 79%

Biophysical and biochemical characterization of a VHH-based IgG-like bi- and trispecific antibody platform

Pekar

Busch

Valldorf

et al. 2020

mAbs

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“…Unfortunately, the EGFR inhibitor erlotinib as a monotherapy failed to produce promising results in several phase II trials, with the objective response rates of 8% to 12%, and the combination of anti-EGFR antibody with chemotherapy in clinical trials did not show a significant improvement of OS and progression-free survival (PFS) in patients with advanced BTCs (9)(10)(11)(12)(13)(14). Recent genetically modified immune cells have illustrated more sensitive and potent antitumor activity than that of a bivalent antibody, even for those with low target antigen expression, which suggested a promising treatment using EGFR-directed genetically modified immune cells in patients with BTCs (15,16).…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of Chimeric Antigen Receptor–Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers

Guo

Feng

Liu

et al. 2018

Clinical Cancer Research

178

126

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This study is an expanded and parallel clinical trial of EGFR-specific chimeric antigen receptor-engineered autologous T (CART) cell immunotherapy (NCT01869166) to assess the safety and activity of CART-EGFR cell therapy in EGFR-positive advanced unresectable, relapsed/metastatic biliary tract cancers (BTC). Patients with EGFR-positive (>50%) advanced unresectable, relapsed/metastatic BTCs were enrolled. Well-produced CART-EGFR cells were infused in a manner of dose escalation after the conditioning treatment with nab-paclitaxel (100-250 mg/m) and cyclophosphamide (15-35 mg/kg). A total of 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) received one to three cycles of CART-EGFR cell infusion (median CART cell dose, 2.65 × 10/kg; range, 0.8-4.1 × 10/kg) within 6 months. The CART-EGFR cell infusion was tolerated, but 3 patients suffered grade ≥3 acute fever/chill. Grade 1/2 target-mediated toxicities including mucosal/cutaneous toxicities and acute pulmonary edema and grade ≥3 lymphopenia and thrombocytopenia related to the conditioning treatment were observed. Of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5-22 months) from the first cycle of treatment. Analysis of data indicated that the enrichment of central memory T cells (Tcm) in the infused CART-EGFR cells improved the clinical outcome. The CART-EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced BTCs. The enrichment of Tcm in the infused CART-EGFR cells could predict clinical response. .

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“…19 We reported the first such immunoligand, ULBP2-BB4 (scFv against CD138), which successfully activated and retargeted NK cells through ULBP2 against CD138-positive multiple myeloma cells both in vitro and in vivo. 20 Subsequently, two additional immunoligands in similar formats, ULBP2-aCEA (scFv against CEA) 21 and ULBP2-aPSMA (scFv against PSMA) 22 and immunoligands fused to other ligands, [23][24][25] validated our approach. Several trispecific immunoconstructs targeting the FcgRIIIa receptor on NK cells have been developed and compared with their bispecific counterparts.…”

Section: Introductionmentioning

confidence: 81%

Mono- and dual-targeting triplebodies activate natural killer cells and have anti-tumor activityin vitroandin vivoagainst chronic lymphocytic leukemia

et al. 2016

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Chronic lymphocytic leukemia (CLL) is the most common form of leukemia that affects B lymphocytes in adults. Natural killer (NK) cells in CLL patients are intrinsically potent but display poor in situ effector functions. NKG2D is an activating receptor found on NK and CD8 C T cells and plays a role in immunosurveillance of CLL. In this study, we developed mono-and dual-targeting triplebodies utilizing a natural ligand for human NKG2D receptor (ULBP2) to retarget NK cells against tumor cells. Triplebodies in both formats showed better ability to induce NK-cell-dependent killing of target cells compared to bispecific counterparts. A mono-targeting triplebody ULBP2-aCD19-aCD19 successfully triggered NK cell effector functions against CLL cell line MEC1 and primary tumor cells in allogenic and autologous settings. Additionally, a dual-targeting triplebody ULBP2-aCD19-aCD33 specific for two distinct tumor-associated antigens was developed to target antigen loss variants, such as mixed lineage leukemia (MLL). Of note, this triplebody exhibited cytotoxic activity against CD19/CD33 double positive cells and retained its binding features even in the absence of one of the tumor antigens. Further, ULBP2-aCD19-aCD19 showed significant in vivo activity in immune-deficient (NSG) mouse model transplanted with CLL cell line as target cells and human immune cells as an effector population providing a proof-of-principle for this therapeutic concept.

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HER2-specific immunoligands engaging NKp30 or NKp80 trigger NK-cell-mediated lysis of tumor cells and enhance antibody-dependent cell-mediated cytotoxicity

Cited by 29 publications

References 49 publications

Biophysical and biochemical characterization of a VHH-based IgG-like bi- and trispecific antibody platform

Biophysical and biochemical characterization of a VHH-based IgG-like bi- and trispecific antibody platform

Phase I Study of Chimeric Antigen Receptor–Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers

Mono- and dual-targeting triplebodies activate natural killer cells and have anti-tumor activityin vitroandin vivoagainst chronic lymphocytic leukemia

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