Blockade of dual immune checkpoint inhibitory signals with a CD47/PD-L1 bispecific antibody for cancer treatment

Wang, Rongjuan; Zhang, Chang; Cao, Yuting; Wang, Junchao; Jiao, Shasha; Zhang, Jiao; Wang, Min; Tang, Peipei; Liang, Wenlu; Yu, Miao; Wang, An; Li, Gang; Zhang, Jinchao; Wang, Mingzhu; Wang, Shuang; Gui, Xun

doi:10.7150/thno.79367

Cited by 13 publications

(17 citation statements)

References 36 publications

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“…Previous reports demonstrated lower binding of an affinity engineered anti-CD47 IgG4 antibody resulted in a better RBC toxicology profile (Thaker et al, 2022). Anti-PD-L1/anti-CD47 bispecific antibodies with significantly lower binding affinity of the anti-CD47 arm compared to the higher affinity anti-PD-L1 arm have been described (Chen et al, 2021;Wang et al, 2023) Such an approach has the potential to provide a better safety profile by preferentially targeting PD-L1/CD47 double positive tumors rather than single positive circulating RBC. QL401 has similar binding affinities and blocking capability for both anti-PD-L1 and anti-CD47 arms.…”

Section: Discussionmentioning

confidence: 98%

“…Because the rationale for combining blocking antibodies to PD-L1 and CD47 was compelling for both improving efficacy and safety, Frontiers in Drug Discovery frontiersin.org we, and others (Wang et al, 2020;Chen et al, 2021;Wang et al, 2023), have taken advantage of conventional antibody engineering to develop human anti-PD-L1/anti-CD47 therapeutic bispecific antibodies. Reported molecular structures vary, but have in common IgG1 or IgG4 backbones using knobs-in-holes technologies.…”

Section: Discussionmentioning

confidence: 99%

“…Reported molecular structures vary, but have in common IgG1 or IgG4 backbones using knobs-in-holes technologies. The source, and molecular characteristics of the CD47 and PD-L1 binding domains are distinct, being derived from standard mouse hybridoma approaches (Wang et al, 2023) or common light chain phage display libraries (Chen et al, 2021) in Fab, or single domain (VHH) format (Wang et al, 2020). QL401 is in a 1 + 1 format on a human IgG4 backbone, with Knob-in-Hole and Protein A binding mutations.…”

Section: Discussionmentioning

confidence: 99%

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Generation of a potent anti-PD-L1-CD47 bispecific antibody with a strong therapeutic and safety profile for cancer immunotherapy

Tang

Schwimmer

et al. 2023

Front. Drug Discov.

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Cell surface molecules PD-L1 and CD47 are potent inhibitors of adaptive and innate anti-cancer immunity. We sought to generate a safe, therapeutic, bispecific antibody specifically targeting, and blocking both PD-L1 and CD47 inhibitory activity. Novel anti-PDL-1 and anti-CD47 antibodies with favorable inhibitory activity, were humanized and constructed into a unique bi-specific antibody intended for clinical use. Previous pre-clinical and clinical studies using anti-CD47 antibodies indicated anemia and thrombocytopenia as potential risks. QL401 is a PD-L1 x CD47 bispecific antibody engineered to reduce effect on red blood cells while retaining potent phagocytic activation of macrophages in vitro and delayed tumor growth in vivo. QL401 comprises three functional components: a PD-L1 binding Fab arm, a CD47 binding scFv arm, and a human IgG4 backbone. The PD-L1 binding arm provides both tumor targeting and blocking of PD-1 for reactivating T cells. The CD47 arm blocks the binding of SIRPα, while the IgG4 Fc retains Fc gamma receptor binding to provide a phagocytic signal. In preclinical efficacy studies, QL401 potently blocked SIRPα to promote phagocytosis of tumor cells with sub-nanomolar potency. In vivo efficacy studies in mouse xenograft tumor models showed QL401 to be comparable or superior to PD-L1 or CD47 monoclonal antibodies alone or in combination. In vitro safety evaluation of QL401 showed significantly reduced binding and phagocytosis of red blood cells, in contrast to CD47 monoclonal antibodies. In addition, QL401 did not induce hemagglutination. In non-human primates, QL401 was well tolerated up to 100 mg/kg without reduction of red blood cells or platelets below the normal range. QL401 is presently in a human phase I safety study.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Generation of a potent anti-PD-L1-CD47 bispecific antibody with a strong therapeutic and safety profile for cancer immunotherapy

Tang

Schwimmer

et al. 2023

Front. Drug Discov.

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“…Based on knobs-into-holes (KIH) platform, Wang et al . developed an anti-CD47 × PD-L1 BsAb 6MW3211, which was designed with a common light chain, exhibiting low affinity to CD47 and high affinity to PD-L1 [ 89 ]. This unique affinity profile allows preferential binding to PD-L1 of tumor cells, suppressing the CD47 signaling pathway [ 89 ].…”

Section: Anti-cd47 × Pd-l1 Bsabmentioning

confidence: 99%

The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling

Li,

Niu,

Zhou

et al. 2024

Cell Commun Signal

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The programmed cell death 1 (PD-1) signaling pathway, a key player in immune checkpoint regulation, has become a focal point in cancer immunotherapy. In the context of cancer, upregulated PD-L1 on tumor cells can result in T cell exhaustion and immune evasion, fostering tumor progression. The advent of PD-1/PD-L1 inhibitor has demonstrated clinical success by unleashing T cells from exhaustion. Nevertheless, challenges such as resistance and adverse effects have spurred the exploration of innovative strategies, with bispecific antibodies (BsAbs) emerging as a promising frontier. BsAbs offer a multifaceted approach to cancer immunotherapy by simultaneously targeting PD-L1 and other immune regulatory molecules. We focus on recent advancements in PD-1/PD-L1 therapy with a particular emphasis on the development and potential of BsAbs, especially in the context of solid tumors. Various BsAb products targeting PD-1 signaling are discussed, highlighting their unique mechanisms of action and therapeutic potential. Noteworthy examples include anti-TGFβ × PD-L1, anti-CD47 × PD-L1, anti-VEGF × PD-L1, anti-4-1BB × PD-L1, anti-LAG-3 × PD-L1, and anti-PD-1 × CTLA-4 BsAbs. Besides, we summarize ongoing clinical studies evaluating the efficacy and safety of these innovative BsAb agents. By unraveling the intricacies of the tumor microenvironment and harnessing the synergistic effects of anti-PD-1/PD-L1 BsAbs, there exists the potential to elevate the precision and efficacy of cancer immunotherapy, ultimately enabling the development of personalized treatment strategies tailored to individual patient profiles.

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“…Recent studies demonstrated that bispecific antibody or fusion protein against both PD‐L1 and CD47 showing better tumour‐cell targeting and stronger therapeutic effect than those of single blockade (Chen, Dominik, et al., 2021; Liu, Liu, et al., 2018). Thus, several studies on CD47/PD‐L1 bispecific antibody are in phase I/II clinical trials (Wang et al., 2023, 2020). However, dual targeting antibody and fusion protein had inherent limitations that curtailed their efficacy in this setting, including poor solid tumour penetration and affinity to ligands respectively (Dahan et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Engineering high‐affinity dual targeting cellular nanovesicles for optimised cancer immunotherapy

Zhang,

Zhao,

Niu

et al. 2023

J of Extracellular Vesicle

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Dual targeting to immune checkpoints has achieved a better therapeutic efficacy than single targeting due to synergistic extrication of tumour immunity. However, most dual targeting strategies are usually antibody dependent which facing drawbacks of antibodies, such as poor solid tumour penetration and unsatisfied affinity. To meet the challenges, we engineered a cell membrane displaying a fusion protein composed of SIRPα and PD‐1 variants, the high‐affinity consensus (HAC) of wild‐type molecules, and with which prepared nanovesicles (NVs). Through disabling both SIRPα/CD47 and PD‐1/PD‐L1 signalling, HAC NVs significantly preserved the phagocytosis and antitumour effect of macrophages and T cells, respectively. In vivo study revealed that HAC NVs had better tumour penetration than monoclonal antibodies and higher binding affinity to CD47 and PD‐L1 on tumour cells compared with the NVs expressing wild‐type fusion protein. Exhilaratingly, dual‐blockade of CD47 and PD‐L1 with HAC NVs exhibited excellent therapeutic efficacy and biosafety. This study provided a novel biomaterial against tumoural immune escape and more importantly an attractive biomimetic technology of protein delivery for multi‐targeting therapies.

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Blockade of dual immune checkpoint inhibitory signals with a CD47/PD-L1 bispecific antibody for cancer treatment

Cited by 13 publications

References 36 publications

Generation of a potent anti-PD-L1-CD47 bispecific antibody with a strong therapeutic and safety profile for cancer immunotherapy

Generation of a potent anti-PD-L1-CD47 bispecific antibody with a strong therapeutic and safety profile for cancer immunotherapy

The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling

Engineering high‐affinity dual targeting cellular nanovesicles for optimised cancer immunotherapy

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