Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity

Wang, Yan; Ni, Haiqing; Zhou, Shuaixiang; He, Kaijie; Gao, Yarong; Wu, Weiwei; Wu, Min; Wu, Zhihai; Qiu, Xuan; Zhou, Ying; Chen, Bingliang; Pan, Donghui; Huang, Chenrong; Li, Mingzhu; Bian, Yicong; Yang, Min; Miao, Liyan; Liu, Junjian

doi:10.1007/s00262-020-02679-5

Cited by 84 publications

(78 citation statements)

References 27 publications

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“…In contrast to antibody-drug conjugates and naked monoclonal antibodies (mAb), bsAbs can be engineered to recruit diverse effector immune cells through coupling with the membrane-associated antigen expressed from cancer cells, and the second antigen expressed in special immune cells, such as natural killer (NK) cells, effector T cells ( 23 ) or immunomodulatory proteins such as cluster of differentiation 47 (CD47) or programmed death receptors 1 (PD-1) ( 24 ). The superior effect might be ascribed to the tumor-directing function generated by bsAbs ( 25 ). Additionally, bsAbs execute their therapeutic effect by binding to receptors expressed on cell surface, without requiring for receptor internalization, which permits to target a disparate population of tumor antigens.…”

Section: Therapeutic Bsabs In Oncologymentioning

confidence: 99%

“…IBI322 is the first anti-CD47/PD-L1 checkpoint bsAb that inhibits both the PD-1/PD-L1 and CD47/SIRP-α pathways, which is used for the treatment of patients with advanced malignancies ( 25 ). Preclinical studies have demonstrated that IBI322 can effectively block CD47/SIRP-α interaction and induce macrophages to phagocytose CD47-expressed tumor cells, which is equivalent to anti-CD47 monoclonal antibody.…”

Section: Bsab Targeting Cd47 and Other Targets That Are Currently In Clinical Trials In Oncologymentioning

confidence: 99%

“…Anti-CD47 antibodies have the tendency to attack normal cells. However, IBI-322 is preferentially distributed in PD-L1-positive tumor cells, thus decreasing the possible adverse effects of this target associated with monospecific anti-CD47 antibodies ( 25 ). In addition, bispecific monoclonal antibody enhances cytotoxicity, antibody selectivity and functional affinity by targeting effector cells directly to tumor cells.…”

Section: Bsab Targeting Cd47 and Other Targets That Are Currently In Clinical Trials In Oncologymentioning

confidence: 99%

“…In addition, bispecific monoclonal antibody enhances cytotoxicity, antibody selectivity and functional affinity by targeting effector cells directly to tumor cells. Preliminary results showed that IBI322 had higher efficacy in vivo , tumor-rich distribution and better safety than the mono-specific anti-CD47 antibody ( 25 ). Bispecific antibody could offer a lower-cost solution for patients compared with two monoclonal antibody combinatorial therapies.…”

Section: Bsab Targeting Cd47 and Other Targets That Are Currently In Clinical Trials In Oncologymentioning

confidence: 99%

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Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Yang

2021

Front. Immunol.

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The prosperity of immunological therapy for cancer has aroused enormous passion for exploiting the novel targets of cancer immunotherapy. After the approval of blinatumomab, a bispecific antibody (bsAb) targeting on CD19 for acute lymphoblastic leukemia, a few of CD47-targeted bsAbs for cancer immunotherapy, are currently in clinical research. In our review of CD47-targeted bsAbs, we described the fundamental of bsAbs. Then, we summarized the information of four undergoing phase I researches, reviewed the main toxicities relevant to CD47-targeted bsAb immunological therapy of on-target cytotoxicity to healthy cells and a remarkable antigen-sink. Finally, we described possible mechanisms of resistance to CD47-targeted bsAb therapy. More clinical researches are supposed to adequately confirm its security and efficacy in clinical practice.

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Section: Therapeutic Bsabs In Oncologymentioning

confidence: 99%

Section: Bsab Targeting Cd47 and Other Targets That Are Currently In Clinical Trials In Oncologymentioning

confidence: 99%

Section: Bsab Targeting Cd47 and Other Targets That Are Currently In Clinical Trials In Oncologymentioning

confidence: 99%

Section: Bsab Targeting Cd47 and Other Targets That Are Currently In Clinical Trials In Oncologymentioning

confidence: 99%

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Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Yang

2021

Front. Immunol.

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“…INBRX-105 is an Fc-silenced anti-PD-L1/4-1BB antibody, and KN046, an anti-PD-L1/CTLA-4 antibody, both in several early trials for various metastatic solid tumors (see Supplementary Table S1 ) [ 139 , 140 ]. Substitution of one Fab arm with one pair of identical nanobodies (Fab-VH2-Fc, Figure 1 d and Table 1 ) is the format of the trivalent bispecific IBI322 targeting CD47(Fab)/PD-L1(VH2) [ 141 ], for which clinical trials were very recently launched in the USA and China (NCT04338659, NCT04328831). TNB-383B is a similar anti-CD3(Fab)/BCMA(VH2) construct by TeneoBio based on the UniAbs platform, which has demonstrated very low CRS rate, solely grade 1–2 occurring in only 21% of the patients (n = 38) enrolled in a phase 1 trial [ 142 , 143 ].…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

Elshiaty

Schindler

Christopoulos

2021

IJMS

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Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future.

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Engineered Bifunctional Proteins for Targeted Cancer Therapy: Prospects and Challenges

Xu²

2021

Advanced Materials

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Bifunctional proteins (BFPs) are a class of therapeutic agents produced through genetic engineering and protein engineering, and are increasingly used to treat various human diseases, including cancer. These proteins usually have two or more biological functions—specifically recognizing different molecular targets to regulate the related signaling pathways, or mediating effector molecules/cells to kill tumor cells. Unlike conventional small‐molecule or single‐target drugs, BFPs possess stronger biological activity but lower systemic toxicity. Hence, BFPs are considered to offer many benefits for the treatment of heterogeneous tumors. In this review, the authors briefly describe the unique structural feature of BFP molecules and innovatively divide them into bispecific antibodies, cytokine‐based BFPs (immunocytokines), and protein toxin‐based BFPs (immunotoxins) according to their mode of action. In addition, the latest advances in the development of BFPs are discussed and the potential limitations or problems in clinical applications are outlined. Taken together, future studies need to be centered on understanding the characteristics of BFPs for optimizing and designing more effective such drugs.

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Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity

Cited by 84 publications

References 27 publications

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

Engineered Bifunctional Proteins for Targeted Cancer Therapy: Prospects and Challenges

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