A Novel Bispecific Antibody, S-Fab, Induces Potent Cancer Cell Killing

Li, Li; He, Ping; Zhou, Changhua; Li, Jing; Dong, Bin; Chen, Siqi; Zhang, Ning; Liu, Yawei; Miao, Ji; Wang, Zhong

doi:10.1097/cji.0000000000000099

Cited by 23 publications

(41 citation statements)

References 30 publications

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“…Proliferation activity was also observed in vivo with the expansion of white blood cells (Figure 4), suggesting that the IL15–IL15α portion of anti-CEA-IL15 causes activation and expansion of immune cells. Interestingly, in contrast to the previous tumor-targeting PFC1, which only binds to integrins on tumor cells or within the tumor microenvironment, anti-CEA-IL15 exerted direct cytotoxic activity against tumor cells (Figure 3), similar to the anti-CEA bispecific antibodies 34,40. These data suggest that anti-CEA-IL15 possesses multiple functions to inhibit tumor growth, including expansion and activation of immune cells, localization to the tumor microenvironment, and direct induction of tumor cytotoxicity.…”

Section: Discussionmentioning

confidence: 67%

“…To generate the recombinant protein anti-CEA-IL15, the anti-CEA nanobody34 was fused with the IgG1 Fc domain and then linked to the IL15Rα–IL15 fusion protein 35. Next, the fusion gene was cloned into the pcDNA3.1(+) vector with an IL-2 signal peptide.…”

Section: Methodsmentioning

confidence: 99%

“…To study the antitumor efficacy of anti-CEA-IL15 in vivo, the human tumor cell LS174T xenograft model was constructed 34. In brief, fresh cultured LS174T cells (1×10 6 ) were mixed with freshly isolated human PBMCs (5×10 6 ) in 200 μL and subcutaneously co-implanted into the right flank of 5-week-old male NOD/SCID mice.…”

Section: Methodsmentioning

confidence: 99%

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A novel multifunctional anti-CEA-IL15 molecule displays potent antitumor activities

Liu¹,

Wang²,

Xing³

et al. 2018

DDDT

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IntroductionInterleukin-15 (IL-15) is an immunomodulatory cytokine. It can activate and expand cytotoxic CD8 T lymphocytes and natural killer cells, leading to potent antitumor effects. Various forms of IL-15 are now in different stages of development for cancer immunotherapy. One of the major issues with IL-15 or IL15–IL15Rα fusion is high toxicity due to systemic activation of immune cells.Materials and methodsIn this study, we engineered a nanobody–cytokine fusion molecule, anti-CEA-IL15, in which an anti-CEA nanobody was linked to an IL15Rα–IL15 fusion. The nanobody–cytokine fusion exhibited multiple mechanisms to kill tumor cells, including promoting immune cell proliferation and directing antibody-dependent cytotoxicity against CEA-positive tumor cells.ResultsIn xenograft models, anti-CEA-IL15 was localized in the tumor microenvironment and exhibited more potent antitumor activities than non-targeting IL-15, supporting potential application of this multifunctional fusion molecule in tumor immunotherapy.ConclusionWe generated and validated a tumortargeting fusion protein, anti-CEA-IL15, which has potent cytokine activity to activate and mobilize the immune system to fight cancer cells. Such strategies may also be applied to other cytokines and tumor-targeting molecules to increase antitumor efficacy.

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Section: Discussionmentioning

confidence: 67%

Section: Methodsmentioning

confidence: 99%

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A novel multifunctional anti-CEA-IL15 molecule displays potent antitumor activities

Liu¹,

Wang²,

Xing³

et al. 2018

DDDT

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“…107 S-Fab, a hybrid of human Fab with a VHH, was constructed by linking a single-domain anti-CEA VHH to a human anti-CD3 Fab. 108 S-Fab can be efficiently expressed and purified from bacteria and showed excellent stability in serum and potent antitumor activity in vitro and in vivo. 108 Another NK cell-retargeting bispecific antibody called BiSS was generated in the binanobody format recently.…”

Section: Heavy-chain-only Antibodiesmentioning

confidence: 99%

“…108 S-Fab can be efficiently expressed and purified from bacteria and showed excellent stability in serum and potent antitumor activity in vitro and in vivo. 108 Another NK cell-retargeting bispecific antibody called BiSS was generated in the binanobody format recently. 89 BiSS can be efficiently expressed and purified from bacteria.…”

Section: Heavy-chain-only Antibodiesmentioning

confidence: 99%

Bispecific antibodies in cancer immunotherapy

Chen

et al. 2016

Human Vaccines & Immunotherapeutics

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Cancer immunotherapy has recently generated much excitement after the continuing success of the immunomodulating anti-CTLA-4 and anti-PD-1 antibodies against various types of cancers. Aside from these immunomodulating antibodies, bispecific antibodies, chimeric antigen receptor T cells, and other technologies are being actively studied. Among the various approaches to cancer immunotherapy, 2 bispecific antibodies are currently approved for patient care. Many more bispecific antibodies are now in various phases of clinical development and will become the next generation of antibody-based therapies. Further understanding of immunology and advances in protein engineering will help to generate a greater variety of bispecific antibodies to fight cancer. Here, we focus on bispecific antibodies that recruit immune cells to engage and kill tumor cells.

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Bispecific light T-cell engagers for gene-based immunotherapy of epidermal growth factor receptor (EGFR)-positive malignancies

Mølgaard

Harwood

Compte

et al. 2018

Cancer Immunol Immunother

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The recruitment of T-cells by bispecific antibodies secreted from adoptively transferred, gene-modified autologous cells has shown satisfactory results in preclinical cancer models. Even so, the approach's translation into the clinic will require incremental improvements to its efficacy and reduction of its toxicity. Here, we characterized a tandem T-cell recruiting bispecific antibody intended to benefit gene-based immunotherapy approaches, which we call the light T-cell engager (LiTE), consisting of an EGFR-specific single-domain V antibody fused to a CD3-specific scFv. We generated two LiTEs with the anti-EGFR V and the anti-CD3 scFv arranged in both possible orders. Both constructs were well expressed in mammalian cells as highly homogenous monomers in solution with molecular weights of 43 and 41 kDa, respectively. In situ secreted LiTEs bound the cognate antigens of both parental antibodies and triggered the specific cytolysis of EGFR-expressing cancer cells without inducing T-cell activation and cytotoxicity spontaneously or against EGFR-negative cells. Light T-cell engagers are, therefore, suitable for future applications in gene-based immunotherapy approaches.

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A Novel Bispecific Antibody, S-Fab, Induces Potent Cancer Cell Killing

Cited by 23 publications

References 30 publications

A novel multifunctional anti-CEA-IL15 molecule displays potent antitumor activities

A novel multifunctional anti-CEA-IL15 molecule displays potent antitumor activities

Bispecific antibodies in cancer immunotherapy

Bispecific light T-cell engagers for gene-based immunotherapy of epidermal growth factor receptor (EGFR)-positive malignancies

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