scFv-Based “Grababody” as a General Strategy to Improve Recruitment of Immune Effector Cells to Antibody-Targeted Tumors

Cai, Zheng; Fu, Ting; Nagai, Yoshinori; Lam, Lian; Yee, Marla; Zhu, Zhiqiang; Zhang, Hongtao

doi:10.1158/0008-5472.can-12-3920

Cited by 14 publications

(26 citation statements)

References 43 publications

(49 reference statements)

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“…One of the monoclonal antibodies, mAb7.16.4, has a shared epitope with trastuzumab, a FDA approved therapeutic agent in clinical use (Zhang et al, 1999). 7.16.4 is active on Erbb2/neu transformed rodent and human tumors in a variety of assays (Cai et al, 2013; Zhang et al, 1999). 7.16.4 has been used in many labs around the world in transgenic animal models of tumors induced by the neu oncogene (Katsumata et al, 1995; Park et al, 2010; Stagg et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers

Nagai

Yan

et al. 2013

Experimental and Molecular Pathology

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p300 is one of several acetyltransferases that regulate FOXP3 acetylation and functions. Our recent studies have defined a complex set of histone acetyltransferase interactions which can lead to enhanced or repressed changes in FOXP3 function. We have explored the use of a natural p300 inhibitor, Garcinol, as a tool to understand mechanisms by which p300 regulates FOXP3 acetylation. In the presence of Garcinol, p300 appears to become disassociated from the FOXP3 complex and undergoes lysosome-dependent degradation. As a consequence of p300's physical absence, FOXP3 becomes less acetylated and eventually degraded, a process that cannot be rescued by the proteasome inhibitor MG132. p300 plays a complex role in FOXP3 acetylation, as it could also acetylate a subset of four Lys residues that repressively regulate total FOXP3 acetylation. Garcinol acts as a degradation device to reduce the suppressive activity of regulatory T cells (Treg) and to enhance the in vivo anti-tumor activity of a targeted therapeutic anti-p185her2/neu (ERBB2) antibody in MMTV-neu transgenics implanted with neu transformed breast tumor cells. Our studies provide the rationale for molecules that disrupt p300 stability to limit Treg functions in targeted therapies for cancers.

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Section: Resultsmentioning

confidence: 99%

Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers

Nagai

Yan

et al. 2013

Experimental and Molecular Pathology

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“…The association constant, dissociation constant and affinity of the complexes consisting of anti-HER2 scFv and recombinant extracellular domain of the HER2 receptor p185 HER2-ECD (Sino Biological, Inc., Beijing, China) were determined by BIAcoreX100 (GE Healthcare) bio-molecular interaction analyzer based on surface plasmon resonance. 49 …”

Section: Methodsmentioning

confidence: 99%

Therapeutic potential of an anti-HER2 single chain antibody–DM1 conjugates for the treatment of HER2-positive cancer

Zhang

Wang

et al. 2017

Sig Transduct Target Ther

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Antibody–drug conjugates (ADCs) take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells, which have become a powerful measure for cancer treatment in recent years. To develop a more effective therapy for human epidermal growth factor receptor 2 (HER2)-positive cancer, we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1. The resulting ADCs, T-SA1–DM1 and T-SA2–DM1 (drug-to-antibody ratio in the range of 3.2–3.5) displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro. In HER2-positive human ovarian cancer xenograft models, T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity. Importantly, three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1. On the basis of the analysis of luminescence imaging, anti-HER2 scFv–HSA fusion antibodies, especially T-SA1, showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab. Collectively, the novel type of ADCs is effective and selective targeting to HER2-positive cancer, and may be a promising antitumor drug candidate for further studies.

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“…Another way to potentially enhance the antitumor efficacy of HER2-targeted mAbs is through the modification of the HER2 single-chain variable fragment (scFv) domain, which binds a target protein other than HER2 30 . Greene et al reported the results of a breast cancer xenograft model, demonstrating the antitumor efficacy of a HER2 scFv and an IFN-γ engineered protein 31 .…”

Section: Her2-directed Mabsmentioning

confidence: 99%

Clinical development of immunotherapies for HER2+ breast cancer: a review of HER2-directed monoclonal antibodies and beyond

Costa¹,

Czerniecki²

2020

npj Breast Cancer

121

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Human epidermal growth factor receptor 2-positive (HER2 +) breast cancer accounts for~25% of breast cancer cases. Monoclonal antibodies (mAbs) against HER2 have led to unparalleled clinical benefit for a subset of patients with HER2 + breast cancer. In this narrative review, we summarize advances in the understanding of immune system interactions, examine clinical developments, and suggest rationales for future investigation of immunotherapies for HER2 + breast cancer. Complex interactions have been found between different branches of the immune system, HER2 + breast cancer, and targeted treatments (approved and under investigation). A new wave of immunotherapies, such as novel HER2-directed mAbs, antibody drug conjugates, vaccines, and adoptive T-cell therapies, are being studied in a broad population of patients with HER2-expressing tumors. The development of immunotherapies for HER2 + breast cancer represents an evolving field that should take into account interactions between different components of the immune system.

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scFv-Based “Grababody” as a General Strategy to Improve Recruitment of Immune Effector Cells to Antibody-Targeted Tumors

Cited by 14 publications

References 43 publications

Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers

Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers

Therapeutic potential of an anti-HER2 single chain antibody–DM1 conjugates for the treatment of HER2-positive cancer

Clinical development of immunotherapies for HER2+ breast cancer: a review of HER2-directed monoclonal antibodies and beyond

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