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Written by | Chunxiao
Allogeneic cell therapy has attracted much attention in the field of cancer treatment and regenerative medicine, but this therapy can reduce its therapeutic efficiency
due to antibody-mediated killing.
Since the 90s of the 20th century, antibody-mediated rejection after organ transplantation has become the focus of transplantation research, rejection is very tricky, it has an important feature is the presence of graft-specific antibodies accompanied by graft damage [1], most immunocompetent patients may eventually experience some form of antibody-mediated
killing.
Therefore, there is an urgent need to develop new methods to provide antibody protection
for cell therapy.
For antibody-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), IgG classes of antibodies mediate target cell killing by their antigen-binding fragment Fab binding epitopes and effector cells or complement activated by their free fragment crystal domain Fc
.
It is hypothesized that CD64, a high-expression IgG Fc high-affinity receptor on transplanted cells, captures monomeric IgG Fc, making Fc
unavailable to effector cells or complement.
On January 2, 2023, Tobias Deuse's research group from the University of California, San Francisco, published a report in Nature Biotechnology titled Protection of cell therapeutics from antibody-mediated killing by A research paper on CD64 overexpression, which establishes a new strategy to protect cells from antibody-mediated killing, which relies on overexpression
of the IgG receptor CD64.
The authors found that CD64 and its intracellular truncated analogue CD64t effectively capture monomeric IgG and occupy its Fc and its target antigen, a finding that has been used
in thyroid epithelial cell, type I diabetes, and CAR-T cell therapy.
The authors first differentiated C57BL/6(B6) mouse-induced pluripotent stem cells (iPSCs) into B6-iEC and expressed Cd64, B6 iECsCd64 Ability to bind mouse free IgG2a-Fc
in a concentration-dependent manner.
In mice, IgG2a and IgG2b are the main homotype antibodies
that mediate ADCC and CDC.
The engineered B6 iECsCD64 is fully resistant to ADCC and CDC damage
.
In the next step, human CD64 was overexpressed in B6 B2m−/−Ciita−/−Cd47+ immunocompromised (HIP)iECs[2] to obtain B6 HIP iECs CD64, B6 HIP iECs CD64 showed IgG1 Fc capture ability in a concentration-dependent manner, and subcutaneous transplantation experiments in ADCC model Rag-1-deficient mice also confirmedCD64 ability
to capture Fc.
Cd64-expressing mouse iECs were indeed able to protect against antibody-mediated killing effects
.
To further evaluate whether the protective effects of CD64 were effective in patients, the authors identified two patients who had received transplants and incubated patient serum samples with iECs and iECs CD64, which are very sensitive to NK cells ADCC and CDC, where iECs are killed very quickly in the CDC assay, and iECsCD64 Once again, it successfully exerted its protective effect against the antibody-mediated killing effect without any cell damage
.
The next goal is to verify the antibody
evasion effect with a humanized IgG1 monoclonal antibody drug that targets CD52, alalanumab, to generate HIP iECs CD52 and HIP iECsCD52, CD64 expressingCD52 targets.
The authors used bioluminescence imaging to evaluate the cell survival rate of the ADCC killing experiment in vivo in NSG immunodeficient mice, injecting NK cells subcutaneously with HIP iECs CD52 or HIP iECs CD52,CD64, when not injected with alemtuzumab, both cell populations showed the same survival rate, and after 2 days of addition of alemtuzumab, the survival rate of HIP iECsCD52 cells decreased sharply, While HIP iECsCD52, CD64 survival remains completely unaffected (Figure 1).
In order to challenge HIP iECs CD52, CD64 more comprehensive immune evasion ability, the authors used allogeneic NK cells, macrophages, neutrophils for killing experiments, and it was proved that HIP iECs CD52 and HIP iECsCD52, CD64 cell survival rate was not affected.
When alaemtuzumab was added to initiate ADCC and CDC, HIP iECs CD52 were rapidly killed, HIP iECsCD52, CD64 were resistant to both allogeneic cell and antibody-mediated
killing.
In vivo testing by subcutaneously injecting HIP iECs CD52 or HIP iECs CD52,CD64 into humanized NSG-SGM3 mice reconstituted with allogeneic CD34+ artificial blood stem cells and adding alemtuzumab on days 0, 1 and 2, all HIP iECs CD52 grafts were quickly rejected, while all HIP iECs CD52, CD64 grafts were all alive, indicating that only HIP iECsCD52, CD64 is fully resistant to all forms of allogeneic cell and antibody-mediated immune attack
.
Hashimoto's thyroiditis is a classic autoimmune disease in which the cytotoxicity of autoantibodies leads to the destruction
of thyroid tissue.
High concentrations of antithyroid peroxidase (TPO) antibodies, predominantly the IgG1 subtype, mediate ADCC and CDC in 90% of patients, reduce thyroid function
.
Anti-TPO antibodies to thyroid epithelial cells (epiCs) have a much
greater chance of surviving and rebuilding organ function if transplanted into hypothyroid patients.
NSG subcutaneously injected epiCs TPO or epi CsTPO, CD64t, human NK cells and anti-TPO, all epiCs TPO grafts were rapidly rejected, while all epiCs TPO, CD64t grafts survived
。 In addition, CD64t grafts were shown to be effective against antibody-mediated killing in both type 1 diabetes mellitus and clinical CAR T-cell therapy-induced antibody responses, and the expression of CD64t did not affect the cytotoxicity
of CAR T cells.
In summary, CD64 or CD64t effectively trapping monomeric IgG, occupying its Fc and then its target antigen is a new strategy to protect cell therapy from antibody-mediated killing, which has achieved initial success
in thyroid epithelial cells, pancreatic β cells, and CAR-T cells.
It breaks through the bottleneck of immune rejection as cell therapy, and may further promote the development of
allogeneic regenerative medicine and tumor immune cell therapy.
Original link:
https://doi.
org/10.
1038/s41587-022-01540-7
Platemaker: Eleven
References
1.
Loupy, A.
& Lefaucheur, C.
Antibody-mediated rejection of solid-organ allografts.
N.
Engl.
J.
Med.
379, 1150–1160 (2018).
2.
Deuse, T.
et al.
Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients.
Nat.
Biotechnol.
37, 252–258 ( 2019).
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