Cancer immunotherapy using anti-TIM3/PD-1 bispecific antibody: a patent evaluation of EP3356411A1

Herrera‐Camacho, Irma; Anaya-Ruı́z, Maricruz; Pérez-Santos, Martín; Peña, Lourdes Millán-Pérez; Bandala, Cindy; Landeta, Gerardo

doi:10.1080/13543776.2019.1637422

Cited by 24 publications

(13 citation statements)

References 25 publications

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“…Previously, the application of the immune system to recognize and eradicate tumors has made significant advance in the clinical use of cancer immunotherapy [ 7 – 9 ]. Notably, the emergence of immune checkpoints inhibitors typically interfered negative regulators of T cell immunity including LAG3 [ 10 – 12 ], CTLA-4 [ 13 , 14 ], PD-1 [ 15 , 16 ], and TIM3 [ 17 , 18 ]. The advent of these “checkpoint inhibitors” has thoroughly altered and improved the former therapies for melanoma, lung cancer, and so on [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Immunoinhibitors Identifies LGALS9 and TGFBR1 as Potential Prognostic Biomarkers for Pancreatic Cancer

Fan

et al. 2020

Computational and Mathematical Methods in Medicine

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Pancreatic cancer (PC) is one of the most deadly cancers worldwide. To uncover the unknown novel biomarker used to indicate early diagnosis and prognosis in the molecular therapeutic field of PC is extremely of importance. Accumulative evidences indicated that aberrant expression or activation of immunoinhibitors is a common phenomenon in malignances, and significant associations have been noted between immunoinhibitors and tumorigenesis or progression in a wide range of cancers. However, the expression patterns and exact roles of immunoinhibitors contributing to tumorigenesis and progression of pancreatic cancer (PC) have not yet been elucidated clearly. In this study, we investigated the distinct expression and prognostic value of immunoinhibitors in patients with PC by analyzing a series of databases, including TISIDB, GEPIA, cBioPortal, and Kaplan-Meier plotter database. The mRNA expression levels of IDO1, CSF1R, VTCN1, KDR, LGALS9, TGFBR1, TGFB1, IL10RB, and PVRL2 were found to be significantly upregulated in patients with PC. Aberrant expression of TGFBR1, VTCN1, and LGALS9 was found to be associated with the worse outcomes of patients with PC. Bioinformatics analysis demonstrated that LGALS9 was involved in regulating the type I interferon signaling pathway, interferon-gamma-mediated signaling pathway, RIG-I-like receptor signaling pathway, NF-kappa B signaling pathway, cytosolic DNA-sensing pathway, and TNF signaling pathway. And TGFB1 was related to mesoderm formation, cell matrix adhesion, TGF-beta signaling pathway, and Hippo signaling pathway. These results suggested that LGALS9 and TGFBR1 might serve as potential prognostic biomarkers and targets for PC.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Immunoinhibitors Identifies LGALS9 and TGFBR1 as Potential Prognostic Biomarkers for Pancreatic Cancer

Fan

et al. 2020

Computational and Mathematical Methods in Medicine

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“…We developed an RO assay to monitor RG7769 target engagement prior to dosing and on‐treatment in the peripheral blood of cancer patients during DE in the clinical trial NP40435. Since RG7769 was designed to primarily engage T cells by binding to cell surface PD‐1 [ 22 , 24 , 32 ], we evaluated the possibility of assessing total PD‐1 on CD3 + T cells in the presence of RG7769. In freshly isolated PBMCs incubated with RG7769 (100 pg/ml➔100 μg/ml), we found that three typical commercial flow cytometry PD‐1 detection antibody clones (EH12.1, NAT105 and J105) showed a strong signal reduction with increasing RG7769 concentrations (Figure 1A,B ).…”

Section: Resultsmentioning

confidence: 99%

“…Studies suggested that in many tumors, upon anti‐PD‐1 therapy, other negative regulators of T cell activation can be co‐expressed, including T cell immunoglobulin and mucin domain‐containing protein 3 (TIM3) [ 16 , 17 ]. More recently, in order to simultaneously target PD‐1 and TIM3 in cancer patients, Roche developed RG7769 (also termed RO7121661), a bi‐specific mAb with an Fc gamma receptor silent IgG 1 P329GLALA backbone [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. RG7769 was designed so that its anti‐PD‐1 affinity is higher than its anti‐TIM3 affinity in order to avoid the antibody from binding to non‐T cells [ 24 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

A human receptor occupancy assay to measure anti‐PD‐1 binding in patients with prior anti‐PD‐1

et al. 2021

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Receptor occupancy (RO) assessment by flow cytometry is an important pharmacodynamic (PD) biomarker in the clinical development of large molecules such as monoclonal therapeutic antibodies (mAbs). The total‐drug‐bound RO assay format directly assesses mAb binding to cell surface targets using anti‐drug detection antibodies. Here, we generated a flow cytometry detection antibody specifically binding to mAbs of the IgG1 P329GLALA backbone. Using this reagent, we developed a total‐drug‐bound RO assay format for RG7769, a bi‐specific P329GLALA containing mAb targeting PD‐1 and TIM3 on T cells. In its fit‐for‐purpose validated version, this RO assay has been used in the Phase‐I dose escalation study of RG7769, informing on peripheral T cell RO and RG7769 antibody binding capacity (ABC). We assessed RG7769 RO in checkpoint‐inhibitor (CPI) naïve patients and anti‐PD‐1 CPI experienced patients using our novel assay. Here, we show that in both groups, complete T cell RO can be achieved (~100%). However, we found that the maximum number of T cell binding sites for RG7769 pre‐dosing was roughly twofold lower in patients recently having undergone anti‐PD‐1 treatment. We show that this is due to steric hindrance exerted by competing mAbs masking the available drug binding sites. Our findings highlight the importance of quantitative mAb assessment in addition to relative RO especially in the context of patients who have previously received anti‐PD‐1 treatment.

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“…TIM3 interacts with multiple ligands including galectin-9, CEACAM1, PtdSer, HMGB1, and causes exhaustion and apoptosis of antigen-specific Th1 cells and CTLs, which correlates with impaired antitumor immune response ( 23 ). The blockade of TIM3 has exhibited beneficial effects in T cell-based immunotherapies in some preclinical studies ( 24 , 25 ). However, more studies showed that antibodies to TIM3 could enhance T cell function, but the efficacy looks moderate or may work best in synergy with PD1/PDL1 blockade ( 26 – 28 ).…”

Section: Discussionmentioning

confidence: 99%

Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells

et al. 2021

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Targeting inhibitory immune checkpoint molecules has significantly altered cancer treatment regimens. T cell immunoglobulin and mucin domain 3 (TIM3) is one of the major inhibitory immune checkpoints expressed on T cells. Blocking the engagement of TIM3 and its inhibitory ligand galectin-9 may potentiate the effects of immunotherapy or overcome the adaptive resistance to the therapeutic blockade of programmed cell death protein 1, cytotoxic T-lymphocyte-associated protein 4, B-and T-lymphocyte attenuator and lymphocyte-activation gene 3, amongst others, as each of these immune checkpoints harbors unique properties that set it apart from the rest. Heavy chain variable fragment (VH)-derived single-domain antibodies (sdAbs) represent a class of expanding drug candidates. These sdAbs have unique advantages, including their minimal size in the antibody class, ease of expression, broad scope for modular structure design and re-engineering, and excellent tumor penetration. In the present study, two sdAbs, TIM3-R23 and TIM3-R53, were generated by immunizing rabbits with the recombinant extracellular domain of TIM3 and applying phage display technology. These sdAbs were easily expressed in mammalian cells. The purified sdAbs were able to bind to both recombinant and cell surface TIM3, and blocked it from binding to the ligand galectin-9. In vivo studies demonstrated that TIM3-R53 was able to potentiate the antitumor activity of chimeric antigen receptor T cells that targeted mesothelin. In conclusion, the results of the present study suggested that TIM3-R53 may be a novel and attractive immune checkpoint inhibitor against TIM3, which is worthy of further investigation.

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Cancer immunotherapy using anti-TIM3/PD-1 bispecific antibody: a patent evaluation of EP3356411A1

Cited by 24 publications

References 25 publications

Comprehensive Analysis of Immunoinhibitors Identifies LGALS9 and TGFBR1 as Potential Prognostic Biomarkers for Pancreatic Cancer

Comprehensive Analysis of Immunoinhibitors Identifies LGALS9 and TGFBR1 as Potential Prognostic Biomarkers for Pancreatic Cancer

A human receptor occupancy assay to measure anti‐PD‐1 binding in patients with prior anti‐PD‐1

Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells

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