IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα, exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement by simultaneously binding to CD47 and CD20 of B cells

Yu, Jifeng; Li, Song; Chen, Dianze; Liu, Dandan; Guo, Huiqin; Yang, Chunmei; Zhang, Wei; Zhang, Li; Zhao, Gui; Tu, Xiaoping; Peng, Liang; Liu, Sijin; Bai, Xing; Song, Yongping; Jiang, Zhongxing; Zhang, Ruliang; Tian, Wenzhi

doi:10.1038/s41375-022-01805-9

Cited by 19 publications

(15 citation statements)

References 15 publications

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“…Due to the nature of the high glycosylation degree of CD47 on the RBCs, the N-linked glycan as a “shield” to block the exposure of the epitopes and prevent the TJC4 binding to human RBCs [ 62 ]. Dual-target bispecific antibodies targeting CD47 and tumor-associated antigens (TAA) or tumor-specific antigens (TSA) have been designed to alleviate hematotoxicity [ 64 – 66 ]. As expected, in this work, anti-CD47 antibody (CC2C6) showed strong binding and hemagglutination with RBCs, whereas the phenomena of anti-CD47 nanobodies hu404 were negligible (Fig.…”

Section: Discussionmentioning

confidence: 99%

BCMA/CD47-directed universal CAR-T cells exhibit excellent antitumor activity in multiple myeloma

Lu,

Li,

et al. 2024

J Nanobiotechnol

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Background BCMA-directed autologous chimeric antigen receptor T (CAR-T) cells have shown excellent clinical efficacy in relapsed or refractory multiple myeloma (RRMM), however, the current preparation process for autologous CAR-T cells is complicated and costly. Moreover, the upregulation of CD47 expression has been observed in multiple myeloma, and anti-CD47 antibodies have shown remarkable results in clinical trials. Therefore, we focus on the development of BCMA/CD47-directed universal CAR-T (UCAR-T) cells to improve these limitations. Methods In this study, we employed phage display technology to screen nanobodies against BCMA and CD47 protein, and determined the characterization of nanobodies. Furthermore, we simultaneously disrupted the endogenous TRAC and B2M genes of T cells using CRISPR/Cas9 system to generate TCR and HLA double knock-out T cells, and developed BCMA/CD47-directed UCAR-T cells and detected the antitumor activity in vitro and in vivo. Results We obtained fourteen and one specific nanobodies against BCMA and CD47 protein from the immunized VHH library, respectively. BCMA/CD47-directed UCAR-T cells exhibited superior CAR expression (89.13-98.03%), and effectively killing primary human MM cells and MM cell lines. BCMA/CD47-directed UCAR-T cells demonstrated excellent antitumor activity against MM and prolonged the survival of tumor-engrafted NCG mice in vivo. Conclusions This work demonstrated that BCMA/CD47-directed UCAR-T cells exhibited potent antitumor activity against MM in vitro and in vivo, which provides a potential strategy for the development of a novel “off-the-shelf” cellular immunotherapies for the treatment of multiple myeloma. Graphic Abstract

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Section: Discussionmentioning

confidence: 99%

BCMA/CD47-directed universal CAR-T cells exhibit excellent antitumor activity in multiple myeloma

Lu,

Li,

et al. 2024

J Nanobiotechnol

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“…Full activation of macrophages requires two conditions: blockade of the CD47 "don't eat me" signal, and activation of the Fc receptor "eat me" signal. The presence of either can only provide a limited macrophage activation [17]. Secondly, blocking the CD47/SIRPα axis can transform tumor-associated macrophages into an antitumor state, and increase tumor macrophage recruitment [18,19].…”

Section: Function and Mechanism Of Cd47/sirpα Axis In Tumor Cellsmentioning

confidence: 99%

“…Application of IMM0306 in treating tumor-implanted SCID mice significantly inhibited tumor growth. Furthermore, in a lymphoma orthotopic model, IMM0306 paired with lenalidomide outperformed any single medicine or rituximab combination with lenalidomide in terms of therapeutic impact [17]. IMM0306 is being tested in two phase I clinical trials in patients with R/R CD20-positive B-cell NHL (NCT04746131 and CTR20192612).…”

Section: Cd47-targeted Bispecific Antibodies Cd47/cd20-targeted Bispe...mentioning

confidence: 99%

“…Besides, when tumor cells express both SIRPα and TSP-1 which inhibit the CD47-SIRPα interaction [70], the effective dose of CD47 antagonist may need to be modified. Additionally, sufficient macrophage activation requires triggering of Fc receptors, hence proper human IgG should be chosen [17]. Even though human IgG1 works better to stimulate macrophages, it also causes immune cells to attack RBCs.…”

Section: Tj011133 (Tjc4 Lemzoparlimab)mentioning

confidence: 99%

“…In order to increase the efficacy and safety of CD47 antagonists, the following strategies of antagonist development may emerge in the future (Fig. 4): (1) Using the strategy of CD47 antagonist prime and maintenance dosing (e.g., 5F9 and IBI-188); (2) Modifying the drug structure of CD47 monoclonal antibody (e.g., AO-176, TJ011133, SRF231, and AK117); (3) Fusion protein of CD47/SIRPa combining with different antibodies, such as CD20, CD19, could be of a promising strategy in the immunotherapy targeting CD47/SIRPa axis (e.g., IMM0306, NI-1701) [17,74]; (4) Development of SIRPα/Fc fusion protein antibodies;…”

Section: Future Perspectivesmentioning

confidence: 99%

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The landscape overview of CD47-based immunotherapy for hematological malignancies

2023

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Extensive clinical and experimental evidence suggests that macrophages play a crucial role in cancer immunotherapy. Cluster of differentiation (CD) 47, which is found on both healthy and malignant cells, regulates macrophage-mediated phagocytosis by sending a "don't eat me" signal to the signal regulatory protein alpha (SIRPα) receptor. Increasing evidence demonstrates that blocking CD47 interaction with SIRPα can enhance cancer cell clearance by macrophages. Additionally, inhibition of CD47/SIRPα interaction can increase antigen cross-presentation, leading to T-cell priming and an activated adaptive antitumor immune response. Therefore, inhibiting CD47/SIRPα axis has a significant impact on tumor immunotherapy. Studies on CD47 monoclonal antibodies are at the forefront of research, and impressive results have been obtained. Nevertheless, hematotoxicity, especially anemia, has become the most common adverse effect of the CD47 monoclonal antibody. More specific targeted drugs (i.e., bispecific antibodies, SIRPα/Fc fusion protein antibodies, and small-molecule inhibitors) have been developed to reduce hematotoxicity. Here, we review the present usage of CD47 antagonists for the treatment of lymphomas and hematologic neoplasms from the perspectives of structure, function, and clinical trials, including a comprehensive overview of the drugs in development.

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Modulating macrophage-mediated programmed cell removal: An attractive strategy for cancer therapy

Li,

Han,

et al. 2024

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα, exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement by simultaneously binding to CD47 and CD20 of B cells

Cited by 19 publications

References 15 publications

BCMA/CD47-directed universal CAR-T cells exhibit excellent antitumor activity in multiple myeloma

BCMA/CD47-directed universal CAR-T cells exhibit excellent antitumor activity in multiple myeloma

The landscape overview of CD47-based immunotherapy for hematological malignancies

Modulating macrophage-mediated programmed cell removal: An attractive strategy for cancer therapy

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