Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

Pan, Zhidi; Chen, Jie; Xiao, Xiaodong; Xie, Yueqing; Jiang, Hua; Zhang, Baohong; Lu, Huili; Yuan, Yunsheng; Han, Lei; Zhou, Yuexian; Zong, Huifang; Wang, Lei; Sun, Rui; Zhu, Jianwei

doi:10.1016/j.apsb.2021.10.028

Cited by 15 publications

(5 citation statements)

References 53 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, we performed a series of biochemical and biological activity assays to evaluate target binding affinities, tumor-directed cytotoxicity, ADCC, the stimulation of IFN-γ secretion, and phagocytosis. This study was facilitated by the significant experience of the authors with protein–protein interactions [ 16 ], bispecific antibody platforms [ 17 , 18 , 19 ], and T-cell-engaging dual function anti-tumor molecules [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

The Generation of Dual-Targeting Fusion Protein PD-L1/CD47 for the Inhibition of Triple-Negative Breast Cancer

et al. 2022

Self Cite

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is a highly aggressive subset of breast cancer with limited therapeutic options. However, its immune evasion mechanisms, characterized by the over-expression of the immune checkpoint molecules PD-L1 and CD47, can be targeted in order to facilitate cancer elimination by cells of innate and adaptive immunity. In this paper, we describe the design, preparation, and evaluation of three novel dual-targeting fusion proteins that were based on the structure frame of prototype IAB (innate and adaptive dependent bispecific fusion protein) and the “Orcutt-type IgG-scFv” molecular model. Three molecules with different spatial conformations were designed to improve antigen–antibody affinity by the addition of Ag–Ab binding sites from the variable region sequences of the anti-PD-L1 monoclonal antibody (mAb) atezolizumab and CV1, a high-affinity receptor of CD47. The results showed that the best-performing among the three proteins designed in this study was protein Pro3; its CV1 N-terminus and Fc domain C-terminus were not sterically hindered. Pro3 was better at boosting T cell proliferation and the engulfment of macrophages than the IAB prototype and, at the same time, retained a level of ADCC activity similar to that of IAB. Through improved design, the novel constructed dual-targeting immunomodulatory protein Pro3 was superior at activating the anti-tumor immune response and has thus shown potential for use in clinical applications.

show abstract

Section: Introductionmentioning

confidence: 99%

The Generation of Dual-Targeting Fusion Protein PD-L1/CD47 for the Inhibition of Triple-Negative Breast Cancer

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…42,43 Zhu et al utilised TF-011 in an alternative context with the construction of a T cell engaging bispeci c antibody (TCB) which utilised TF-011 light chains linked by their C-termini to anti-CD3 (OKT3) scFv. 44 They showed signi cant anti-tumour activity both in vitro and in vivo with the anti-TF/CD3 TCB. Alternatively, while traditional CAR utilise an immunoglobulin-derived scFv fragment, a promising non-traditional 3 rd generation anti-TF CAR T cell was created utilising the Factor VII light chain rather than a scFv.…”

Section: Discussionmentioning

confidence: 97%

Conversion of anti-tissue factor antibody sequences to chimeric antigen receptor and bi- specific T cell engager format

SC,

Halpin,

Tan

et al. 2024

Preprint

View full text Add to dashboard Cite

Background The efficacy of antibody-targeted therapy of solid cancers is limited by the lack of consistent tumour-associated antigen expression. However, tumour associated antigens shared with non-malignant cells may still be targeted using conditionally activated-antibodies or by chimeric antigen receptor (CAR) T cells or CAR NK cells activated either by the tumour microenvironment or following 'unlocking' via multiple antigen-recognition. In this study we have focused on tissue factor (TF; CD142), a type I membrane protein present on a range of solid tumours as a basis for future development of conditionally-activated BiTE or CAR T cells. TF is frequently upregulated on multiple solid tumours providing a selective advantage for growth, immune evasion and metastasis, as well as contributing to the pathology of thrombosis via the extrinsic coagulation pathway. Methods Two well-characterised anti-TF monoclonal antibodies hATR-5 and TF8-5G9 maintained their nanomolar affinities following conversion into a single chain (scFv) format. maintained their nanomolar affinities following conversion into a single chain (scFv) format.CD28-CD3-based CAR or CD3-based BiTE format based on the anti-TF mAb scFv constructs were able to activate T cells. Two well-characterised anti-TF monoclonal antibodies hATR-5 and TF8-5G9 maintained their nanomolar affinities following conversion into a single chain (scFv) format. CD28-CD3-based CAR or CD3-based BiTE format based on the anti-TF mAb scFv constructs were able to activate T cells. Conclusion Because of the broad expression of TF on a range of solid cancers, anti-TF antibody formats provide a useful addition for the development of conditionally activated biologics for antibody and cellular-based therapy.

show abstract

“…Thus, bispecific antibodies with bivalent binding domain to tumor antigen might be more potent to eliminate tumors ( Santich et al, 2020 ). Immune checkpoint inhibitors, including cytotoxic T cell lymphocyte antigen-4 antibody and programmed death-1 antibody, could block the receptor to down-regulate T cells activation and were used to treat colorectal cancer ( Chang et al, 2017 ; Pan et al, 2021 ). Combination CD3×EpCAM BsAb with the immune checkpoint inhibitor with CD3×EpCAM BsAb might be more helpful to improve the anti-tumor efficacy in future work.…”

Section: Discussionmentioning

confidence: 99%

IgG-like Bispecific Antibody CD3×EpCAM Generated by Split Intein Against Colorectal Cancer

et al. 2022

Self Cite

View full text Add to dashboard Cite

Background: Colorectal cancer is a commonly diagnosed cancer with high mortality worldwide. Postoperative recidivation and metastasis still are the main challenges in clinical treatments. Thus, it is urgent to develop new therapies against colorectal cancer. Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in colorectal cancer cells and strongly associated with cancer development. Bispecific antibody (BsAb) is a kind of promising immunotherapy, which could recognize T cells and cancer cells simultaneously to achieve the anti-tumor effects.Methods: A bispecific antibody targeting EpCAM and CD3 with IgG format was genereated by split intein based on the Bispecific Antibody by Protein Splicing” platform. In vitro, the affinity of CD3×EpCAM BsAb was determined by Biolayer interferometry, its cytotoxicity was detected by LDH release assay, T cell recruitment and activation was detected by Flow Cytometry. In vivo, its pharmacokinetic parameters were detected, and anti-tumor effects were evaluated on the tumor cell xenograft mouse model.Results: The results showed that the CD3×EpCAM BsAb could activate and recruit T cells via binding colorectal cells and T cells, which could lead to more potent cytotoxicity to various colorectal cell lines than its parent EpCAM monoclonal antibody (mAb) in vitro. The CD3×EpCAM BsAb had similar pharmacokinetic parameters with EpCAM mAb and inhibits tumor growth on the SW480 tumor cell xenograft mouse model.Conclusion: The CD3×EpCAM BsAb could be a promising candidate for colorectal cancer treatment.

show abstract

Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

Cited by 15 publications

References 53 publications

The Generation of Dual-Targeting Fusion Protein PD-L1/CD47 for the Inhibition of Triple-Negative Breast Cancer

The Generation of Dual-Targeting Fusion Protein PD-L1/CD47 for the Inhibition of Triple-Negative Breast Cancer

Conversion of anti-tissue factor antibody sequences to chimeric antigen receptor and bi- specific T cell engager format

IgG-like Bispecific Antibody CD3×EpCAM Generated by Split Intein Against Colorectal Cancer

Contact Info

Product

Resources

About