Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Yang, Yan; Yang, Zheng; Yang, Yun

doi:10.3389/fimmu.2021.686031

Cited by 24 publications

(22 citation statements)

References 75 publications

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“…The low-affinity binding to CD47 and the associated increased tumor selectivity results in a higher safety profile of the described bsAbs. Currently, four of these antibodies are in clinical or preclinical study ( 74 ). In the case of HCP-LCE, the antibody would inhibit PD-L1 in an EGFR-dependent manner, which could significantly reduce side effects.…”

Section: Discussionmentioning

confidence: 99%

A Generic Strategy to Generate Bifunctional Two-in-One Antibodies by Chicken Immunization

Harwardt

Bogen²,

Carrara³

et al. 2022

Front. Immunol.

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Various formats of bispecific antibodies exist, among them Two-in-One antibodies in which each Fab arm can bind to two different antigens. Their IgG-like architecture accounts for low immunogenicity and also circumvents laborious engineering and purification steps to facilitate correct chain pairing. Here we report for the first time the identification of a Two‐in‐One antibody by yeast surface display (YSD) screening of chicken-derived immune libraries. The resulting antibody simultaneously targets the epidermal growth factor receptor (EGFR) and programmed death‐ligand 1 (PD-L1) at the same Fv fragment with two non-overlapping paratopes. The dual action Fab is capable of inhibiting EGFR signaling by binding to dimerization domain II as well as blocking the PD-1/PD-L1 interaction. Furthermore, the Two-in-One antibody demonstrates specific cellular binding properties on EGFR/PD-L1 double positive tumor cells. The presented strategy relies solely on screening of combinational immune-libraries and obviates the need for any additional CDR engineering as described in previous reports. Therefore, this study paves the way for further development of therapeutic antibodies derived from avian immunization with novel and tailor-made binding properties.

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Section: Discussionmentioning

confidence: 99%

A Generic Strategy to Generate Bifunctional Two-in-One Antibodies by Chicken Immunization

Harwardt

Bogen²,

Carrara³

et al. 2022

Front. Immunol.

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“…Consequently, dual-targeting CD47xPD-L1 bsAbs, enabling the preferential inhibition of CD47 on PD-L1-positive cells, are being tested as an alternative approach [ 46 ]. There are currently a number of bispecific antibodies targeting CD47 and PD-1/PD-L1 for the treatment of patients with various kinds of cancers [ 47 ], such as HX009 (NCT04886271), IBI322 (NCT04338659), PF-07257876 (NCT04881045) [ 48 ], SG12473 (CTR20211029), etc. Among them, the anti-PD-1/CD47 bsAb HX009 developed by Hangzhou Hanx Biopharmaceutics, Inc. to treat patients with advanced solid tumors, including gastric cancer, colorectal cancer, and liver cancer, has shown promising clinical data.…”

Section: Discussionmentioning

confidence: 99%

The Generation of Dual-Targeting Fusion Protein PD-L1/CD47 for the Inhibition of Triple-Negative Breast Cancer

et al. 2022

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Triple-negative breast cancer (TNBC) is a highly aggressive subset of breast cancer with limited therapeutic options. However, its immune evasion mechanisms, characterized by the over-expression of the immune checkpoint molecules PD-L1 and CD47, can be targeted in order to facilitate cancer elimination by cells of innate and adaptive immunity. In this paper, we describe the design, preparation, and evaluation of three novel dual-targeting fusion proteins that were based on the structure frame of prototype IAB (innate and adaptive dependent bispecific fusion protein) and the “Orcutt-type IgG-scFv” molecular model. Three molecules with different spatial conformations were designed to improve antigen–antibody affinity by the addition of Ag–Ab binding sites from the variable region sequences of the anti-PD-L1 monoclonal antibody (mAb) atezolizumab and CV1, a high-affinity receptor of CD47. The results showed that the best-performing among the three proteins designed in this study was protein Pro3; its CV1 N-terminus and Fc domain C-terminus were not sterically hindered. Pro3 was better at boosting T cell proliferation and the engulfment of macrophages than the IAB prototype and, at the same time, retained a level of ADCC activity similar to that of IAB. Through improved design, the novel constructed dual-targeting immunomodulatory protein Pro3 was superior at activating the anti-tumor immune response and has thus shown potential for use in clinical applications.

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“…Unique inhibitors of the CD47-SIRP⍺ axis include monoclonal antibodies against CD47 (magrolimab also known as Hu5F9-G4, evorpacept, CC-90002, SRF231, letaplimab, lemzoparlimab, AO-176, TJ011133, SHR-1603, and ZL-1201), monoclonal antibodies against SIRP⍺ (BI765063, GS-0189, CC-95251), and recombinant SIRP⍺-Fc fusion proteins (TTI-621, TTI-622, and evorpacept) [ 213 , 214 ]. Bispecific antibodies are also emerging with secondary targets including CD19 (TG-1801), CD20 (IMM0306), CD40L (SL-172154), PD-1 (HX009), and PD-L1 (IBI322) [ 215 ].…”

Section: Targeting Strategies Against Myeloid Cells For Cancer Immuno...mentioning

confidence: 99%

Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy

Wang

Johnson²,

Gatti‐Mays

et al. 2022

J Hematol Oncol

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Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein 4 provide deep and durable treatment responses which have revolutionized oncology. However, despite over 40% of cancer patients being eligible to receive immunotherapy, only 12% of patients gain benefit. A key to understanding what differentiates treatment response from non-response is better defining the role of the innate immune system in anti-tumor immunity and immune tolerance. Teleologically, myeloid cells, including macrophages, dendritic cells, monocytes, and neutrophils, initiate a response to invading pathogens and tissue repair after pathogen clearance is successfully accomplished. However, in the tumor microenvironment (TME), these innate cells are hijacked by the tumor cells and are imprinted to furthering tumor propagation and dissemination. Major advancements have been made in the field, especially related to the heterogeneity of myeloid cells and their function in the TME at the single cell level, a topic that has been highlighted by several recent international meetings including the 2021 China Cancer Immunotherapy workshop in Beijing. Here, we provide an up-to-date summary of the mechanisms by which major myeloid cells in the TME facilitate immunosuppression, enable tumor growth, foster tumor plasticity, and confer therapeutic resistance. We discuss ongoing strategies targeting the myeloid compartment in the preclinical and clinical settings which include: (1) altering myeloid cell composition within the TME; (2) functional blockade of immune-suppressive myeloid cells; (3) reprogramming myeloid cells to acquire pro-inflammatory properties; (4) modulating myeloid cells via cytokines; (5) myeloid cell therapies; and (6) emerging targets such as Siglec-15, TREM2, MARCO, LILRB2, and CLEVER-1. There is a significant promise that myeloid cell-based immunotherapy will help advance immuno-oncology in years to come.

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Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Cited by 24 publications

References 75 publications

A Generic Strategy to Generate Bifunctional Two-in-One Antibodies by Chicken Immunization

A Generic Strategy to Generate Bifunctional Two-in-One Antibodies by Chicken Immunization

The Generation of Dual-Targeting Fusion Protein PD-L1/CD47 for the Inhibition of Triple-Negative Breast Cancer

Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy

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