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Bispecific Antibody in Finding Tumor Cells in Patients With Colorectal Cancer

ABSTRACT: RATIONALE: Diagnostic procedures, such as radionuclide imaging using bispecific antibody, may help find colorectal cancer cells and learn the extent of disease. PURPOSE: This phase I trial is studying how well a bispecific antibody works in finding tumor cells in patients with colorectal cancer.

DISEASE(S): Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2071852 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

Project description:CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. Interestingly, IFNγ functions by stimulating the expression of T cell killing-related molecules in a cell type-specific manner. Additionally, by assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a novel and critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Moreover, proper fucosylation of CD123 is required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T cell engaging CD3-bispecific antibody therapies.

2020-11-12 | GSE159547 | GEO

T-cell exhaustion induced by continuous bispecific antibody exposure is ameliorated by treatment-free intervals

Project description:T-cell-recruiting bispecific antibody therapy has yielded promising results in patients with hematologic malignancies, however, resistance and subsequent relapse remains a major challenge. T-cell exhaustion induced by persistent antigen stimulation or tonic receptor signaling has been reported to compromise outcomes of T-cell based immunotherapies. The impact of continuous exposure to bispecifics on T-cell function, however, remains poorly understood. In relapsed/refractory B-cell precursor acute lymphoblastic leukemia patients, 28-day continuous infusion with the CD19xCD3 bispecific antibody blinatumomab led to declining T-cell function. In an in vitro model system, mimicking 28-day continuous infusion with the half-life-extended CD19xCD3 bispecific AMG 562, we identified hallmark features of exhaustion arising over time. Continuous AMG 562 exposure induced progressive loss of T-cell function (day 7 vs day 28 mean specific lysis: 88.4% vs 8.6%; n = 6; p = .0003). Treatment-free intervals (TFIs), achieved by AMG 562 withdrawal, were identified as powerful strategy for counteracting exhaustion. TFIs induced strong functional reinvigoration of T cells (continuous vs TFI specific lysis on day 14: 34.9% vs 93.4%; ± SEM; n = 6; p < .0001) and transcriptional reprogramming. Furthermore, use of a TFI led to improved T-cell expansion and tumor control in vivo. Our data demonstrate the relevance of T-cell exhaustion in bispecific antibody therapy and highlight that T cells can be functionally and transcriptionally rejuvenated with TFIs. In view of the growing number of bispecific molecules being evaluated in clinical trials, our findings emphasize the need to consider and evaluate TFIs in application schedules to improve clinical outcomes.

2022-07-26 | GSE196463 | GEO

Single-cell mRNA sequencing of anti-PD-1 GITR-L bispecific antibody treated CT26 mouse tumor model infiltrating leukocytes

Project description:Single-cell mRNA sequencing of anti-PD-1 GITR-L bispecific antibody treated CT26 mouse tumor model infiltrating leukocytes

2021-12-20 | GSE190105 | GEO

Immunoscintigraphy Using Radiolabeled Monoclonal Antibody in Finding Tumor Cells in Patients With Colorectal Cancer

Project description:RATIONALE: Diagnostic procedures, such as immunoscintigraphy, using a radiolabeled monoclonal antibody may help find and diagnose colorectal cancer. PURPOSE: This clinical trial is studying how well immunoscintigraphy using a radiolabeled monoclonal antibody works in finding tumor cells in patients with colorectal cancer.

| 2053043 | ecrin-mdr-crc

Dual checkpoint blockade of CD47 and PD-L1 using a novel affinity-tuned bispecific antibody maximizes anti-tumor immunity (NanoString)

Project description:A novel affinity-tuned dual-checkpoint bispecific antibody with potent PD-L1 and moderate CD47 affinity was designed to improve the selectivity to TME and thus enhance antitumor immunity and efficacy. The gene expression analysis using Nanostring platform was performed to examine the immune cell modulation in TME following the CD47/PD-L1 bispecific treatment.

2021-10-13 | GSE177053 | GEO

Dual checkpoint blockade of CD47 and PD-L1 using a novel affinity-tuned bispecific antibody maximizes anti-tumor immunity (scRNA-Seq)

Project description:A novel affinity-tuned dual-checkpoint bispecific antibody with potent PD-L1 and moderate CD47 affinity was designed to improve the selectivity to TME and thus enhance antitumor immunity and efficacy. The scRNAseq analysis was performed to examine the immune cell modulation in TME following the CD47/PD-L1 bispecific treatment.

2022-04-20 | GSE180296 | GEO

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

Project description:A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

| PRJNA669680 | ENA

A Multipronged Unbiased Strategy Guides the Development of an anti-EGFR/EPHA2 Bispecific Antibody for Combination Cancer Therapy

Project description:Purpose: Accumulating analyses of pro-oncogenic molecular mechanisms triggered a rapid development of targeted cancer therapies. Although many of these treatments produce impressive initial responses, eventual resistance onset is practically unavoidable. One of the main approaches for preventing this refractory condition relies on the implementation of combination therapies. This includes dual-specificity reagents that affect both of their targets with a high level of selectivity. Unfortunately, selection of target combinations for these treatments is often confounded by limitations in our understanding of tumor biology. Here, we describe and validate a multipronged unbiased strategy for predicting optimal co-targets for bispecific therapeutics. Experimental design: Our strategy integrates ex-vivo genome-wide loss of function screening, BioID interactome profiling and gene expression analysis of patient data to identify the best fit co-targets. Final validation of selected target combinations is done in tumorsphere cultures and xenograft models. Results: Integration of our experimental approaches unambiguously pointed towards EGFR and EPHA2 tyrosine kinase receptors as molecules of choice for co-targeting in multiple tumor types. Following this lead, we generated a human bispecific anti-EGFR/EPHA2 antibody that, as predicted, very effectively suppresses tumor growth, compared to its prototype anti-EGFR therapeutic antibody, cetuximab. Conclusion: Our work not only presents a new bispecific antibody with a high potential for being developed into clinically-relevant biologics, but more importantly, successfully validates a novel unbiased strategy for selecting biologically optimal target combinations. This is of a significant translational relevance, as such multifaceted unbiased approaches are likely to augment the development of effective combination therapies for cancer treatment.

2023-02-23 | GSE171920 | GEO

Study of Activated Cytokine-induced Killer Armed With Bispecific Antibody for Advanced Colorectal Cancer

Project description:This is a phase II Randomized comparison clinical trial of activated CIK armed with anti-CD3-MUC1 bispecific antibody for advanced colorectal cancer. And the aim of this research is to study the clinical efficacy and safety of activated CIK armed with anti-CD3-MUC1 bispecific antibody for colorectal cancer.

| 2272861 | ecrin-mdr-crc

An Unbiased Strategy for Selecting Effective Combinations of Therapeutic Targets Supports the Development of a Novel Bispecific Antibody with Tumor-Suppressing Properties

Project description:Recent progress in dissecting molecular mechanisms essential for the survival and propagation of cancer cells triggered rapid development of targeted therapies. Although many of these therapies produce impressive initial responses in tumor suppression, the onset of resistance is practically unavoidable. One of the main approaches for preventing this refractory condition relies on the development of effective combination therapies. Unfortunately, selection of optimal targets for combinatorial treatments is often confounded by limitations in our understanding of tumor biology. Here, we describe an unbiased comprehensive strategy that combines ex-vivo shRNA-based genome wide screening, proteomic profiling using BioID and patient tumor sequencing data analyses to overcome current challenges in identifying the best fit co-targeting agents. Integrating these strategies, we selected EGFR and EPHA2 receptors as molecules of choice for co-targeting in cancer cells, and generated a bispecific fully humanized anti-EGFR/EPHA2 antibody with druggable bioanalytical properties that very effectively suppresses tumor growth compared to its prototype therapeutic anti-EGFR antibody, cetuximab. Despite the overactivation of EGFR signaling in multiple malignancies, the therapeutic applicability of cetuximab is limited due to frequent resistance and could benefit from being used in a combination with another targeted compound. Our analysis indicates that EGFR and EPHA2 expression positively correlate in various cancer types and thus, are available for co-targeting in most tumors. Therefore, our work not only presents an efficient unbiased strategy for selecting optimal targets for combination therapies, but also describes a novel bispecific antibody, which has a high potential for being developed into a new clinically-relevant biologics effective in a broad variety of malignancies.

2023-01-27 | PXD023034 | Pride

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