A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL

Zhao, Lijun; Li, Shuhong; Wei, Xiaoyi; Qi, Xuexiu; Liu, Dong; Liu, Lei; Wen, Feiqiu; Zhang, Jishuai; Wang, Feng; Liu, Zelin; Cao, Yu

doi:10.1182/blood.2022016243

Cited by 30 publications

(13 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, access of the 2Rs15 to SP34 C-terminus or 3VGR19 to S171-D173 of SP34 LC could likely provide the necessary geometry to enable optimal target and T-cell interactions. It is worth noting the requirement of personalized optimization of the tsAb design if targeting other TAAs, as another work suggested the optimal structure of CD19/CD22/CD3 tsAb was obtained by fusing both CD19- and CD22-specific antibodies to the C-terminus of the HC and LC of SP34 Fab 58 . Collectively, this study underscores the importance of optimizing the IS geometry, which directly affects tsAb activity.…”

Section: Discussionmentioning

confidence: 99%

A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy

Liu¹,

Qi²,

Wei³

et al. 2022

Theranostics

View full text Add to dashboard Cite

Rationale: T-cell-redirecting bispecific antibodies (bsAbs) and trispecific antibodies (tsAbs) designed to recognize different epitopes or antigens have emerged as promising cancer therapies. Current approaches are all designed to include another antibody specific to the site of the primary antibody, and the molecular structures are generally established. However, the dimensions of target molecule and epitope location play a key role in the efficiency of the immunological synapse (IS) formation and subsequent T-cell-redirecting activities, therefore the connection flexibility of these antibodies determines the geometries of different formats of these molecules and will have a major impact on the efficacy. Methods: We describe a novel recombination strategy using various linker designs to site-specifically fuse anti-Her2 (2Rs15) or anti-VEGFR2 (3VGR19) nanobodies to different positions of the anti-CD3 antibody fragment (Fab, SP34). Based on the comparison among the various antigen-specific bsAbs, we could determine the desired fusion site of each nanobody to SP34, and further ensure the optimal structure of tsAbs with synergistic dual-antigen enhanced T-cell-redirecting activities. Results: This approach allows precise control of the formation of IS between Her2- and/or VEGFR2-expressing cancer cells and T cells, to obtain the optimal structure of the Her2/VEGFR2/CD3 tsAb without the need to map antibody-binding epitopes. Optimization of Her2/VEGFR2/CD3 tsAb results in enhanced T-cell-redirecting in vitro and in vivo antitumor efficacy compared with the corresponding bsAbs alone or in combination, and the potency to overcome tumor relapse due to antigen escape or resistance to Herceptin and Cyramza therapy. Conclusion: The novel design strategy for developing tsAbs using a site-specific recombination approach represents a promising platform for immuno-oncology and in applications other than cancer therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy

Liu¹,

Qi²,

Wei³

et al. 2022

Theranostics

View full text Add to dashboard Cite

show abstract

“…Bispeci c antibody therapy has led to signi cant advances in tumor treatment [42]. Targeting of CD19 and CD3 in acute lymphoblastic leukemia formed the basis for the world's rst FDA-approved bispeci c antibody immunotherapy [43]. Bispeci c antibodies are structurally similar to monoclonal antibodies, containing two scFvs derived from monoclonal antibodies that are linked with a exible peptide [44].…”

Section: Discussionmentioning

confidence: 99%

Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in Colorectal cancer

Chen

Zhu

Jiang

et al. 2023

Preprint

View full text Add to dashboard Cite

Background Chimeric antigen receptor- T (CAR-T) cell therapy is an efficient therapeutic strategy for specific hematological malignancies. However, positive outcomes of this novel therapy in treating solid tumors are restricted by the immunosuppressive tumor microenvironment (TME), wherein, checkpoint molecular programmed death-1 (PD-1)/PD-L1 signaling directly inhibits T-cell responses. Although checkpoint immunotherapy succeeds in increasing the number of T cells produced to control tumor growth, the desired effect is mitigated by the action of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) present in the TME. Previous studies have confirmed that targeting triggering-receptor-expressed on myeloid cells 2 (TREM2) on TAMs and MDSCs enhances the outcomes of anti-PD-1 immunotherapy. Methods Therefore, we constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs. Results We found that the PD-1-TREM2-targeting scFv inhibited the activation of the PD-1/PD-L1 pathway. In addition, these secreted scFvs blocked the binding of ligands to TREM2 receptors present on MDSCs and TAMs, reduced the proportion of MDSCs and TAMs, and enhanced T-cell effector function, thereby mitigating immune resistance in the TME. Meanwhile, the scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life. Conclusions The PD-1-TREM2 scFv-secreting CAR-T cells exhibited substantially potent anti-tumor effects, evidenced by highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.

show abstract

“…IL-4 is a Th2 cytokine that has a wide range of biological effects, especially with regard to immune responses ( 38 ). In the treatment of B-ALL with CD19/CD22/CD3 trispecific antibody, IL-4 was up-regulated in the treatment group ( 39 ). Another study showed that Man-CTS-TCL NPs increased the concentration of IL-4 concentration compared with the control group ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Enhancedanti-tumor efficacy through a combination of intramuscularly expressed DNA vaccine and plasmid-encoded PD-1 antibody

et al. 2023

View full text Add to dashboard Cite

Immune check inhibitors (ICIs) have moderate response rates (~20%–30%) in some malignancies clinically, and, when used in combination with other immunotherapeutic strategies such as DNA tumor vaccines, there is evidence to suggest that they could optimize the efficacy of cancer treatment. In this study, we validated that intramuscular injection of plasmid DNA (pDNA) encoding OVA combined with pDNA encoding α-PD-1 (abbreviated as α-PD-1 in the following treatment groups) may enhance therapeutic efficacy by means of in situ gene delivery and enhanced muscle-specific potent promoter. Mice treated with pDNA-OVA or pDNA-α-PD-1 alone showed weak tumor inhibition in the MC38-OVA-bearing model. In comparison, the combined treatment of pDNA-OVA and pDNA-α-PD-1 resulted in superior tumor growth inhibition and a significantly improved survival rate of over 60% on day 45. In the B16-F10-OVA metastasis model, the addition of the DNA vaccine enhanced resistance to tumor metastasis and increased the populations of CD8+ T cells in blood and spleen. In conclusion, the current research shows that a combination of pDNA-encoded PD-1 antibody and DNA vaccine expressed in vivo is an efficient, safe, and economical strategy for tumor therapy.

show abstract

A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL

Cited by 30 publications

References 56 publications

A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy

A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy

Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in Colorectal cancer

Enhancedanti-tumor efficacy through a combination of intramuscularly expressed DNA vaccine and plasmid-encoded PD-1 antibody

Contact Info

Product

Resources

About