This program aims to develop anti-CD40L therapeutic monoclonal antibody for immuno-oncology.
Anti-CD40L antibody targets CD40/TNFRSF5 receptors. It produces pleiotropic effects in various cells and biological processes including immune response, thrombosis and atherogenesis. Data implicate that soluble CD40L is fully capable of activating DCs and inducing T-cell responses. The CD40L fusion protein can also trigger CD40-dependent B-cell proliferation. The use of agonistic anti-CD40L antibodies to induce CD40 signaling on DCs can substitute for CD4+ T-cell to help and directly stimulate a specific CD8+ CTL response, highlighting a clear rationale for CD40-based cancer immunotherapy. In this case, anti-CD40L antibody has great potential to be widely applied in the efficient treatment of various diseases. All the research results have been patented.
CD40L in Cancer Research
• CD4+ T-helper cells and CD40L can mediate CD40 costimulation of DCs, which is critical for the generation of antitumor T-cell responses.
Fig.1 CD4+ T-helper cells and CD40L can mediate CD40 costimulation of DCs.1
• The expression level of serum sCD40L is up-regulated in cancer patients, compared with healthy donors (HD).
Serum sCD40L levels in HDs were compared with patients with metastatic breast cancer (Breast Ca), metastatic
colon cancer (Colon Ca), or first-degree (1°) prostate cancer (Prostate Ca) before any treatment.
• The effect of AdCD40L therapy on subcutaneous and orthotopic tumors
Fig.2 The effect of AdCD40L therapy on subcutaneous and orthotopic tumors.2
CD40L
CD40L is a member of the tumor necrosis factor (TNF) family and a cell surface interaction molecule. It is a 261-amino-acid type II membrane glycoprotein, mainly expressed as CD4+-T-cell subset. CD40L is an early activation marker of T lymphocytes, and CD40L expression is induced shortly after T-cell activation. The CD40-CD40L pathway has been throughly investigated and is believed to play multiple functional roles in a healthy immune system. The CD40–CD40L interactions at DC–T cell and T cell–T cell interface is shown here (see fig1).
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CD40 is expressed on the surface of numerous immune and non-immune cells, whereas CD40L is expressed primarily on activated CD4+ T cells and platelets.
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The CD40/CD40L system allows interactions between immune cells and/or non-immune cells.
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Cognate interactions between CD40 and CD40L has impacts on humoral immunity, cell mediated immunity, and
inflammation.
Fig.3 CD40–CD40L interactions at DC-T cell and T cell-T cell interface.3
Mechanism of Action for Anti-CD40L Antibody
The costimulatory molecule CD40L is primarily expressed on activated CD4+ T lymphocytes. Anti-CD40L binds to the CD40L available at T cell, and it blocks the interaction with CD40 receptor, which presents on APC. It is believed that treatments with anti-CD40L (CD154) or anti-CD40 mAb, either alone or combined with other molecules, can downregulate T cell proliferation, Th1 cytokine production, and antibody secretion.
Fig.4 Anti-CD40L interaction and effects on T cells.3
Indication
CD40–CD40L interactions play a critical role in regulating immunal responses. Blockade of CD40L by using Abs demonstrates positive effects in patients with multiple diseases. Here, we list some diseases in which the CD40-CD40L interactions may play a role.
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Disease
|
Explanation
|
|
Rheumatic
disease (SLE&RA)
|
• CD40L
expression in lupus B cells is very important to the development of SLE
• CD40L is
highly expressed on T cells that are extracted from patients with RA. Treatment
with anti-CD40L mAb suppresses the development of collagen-induced RA.
|
|
AIDS
|
CD40L is necessary for immune defense against human immunodeficiency virus and opportunistic infections; this may cover the similarities of clinical manifestations of AIDS to those of the congenital CD40L deficiency (hyper IgM syndrome).
|
|
Cancer
|
Efforts are being made to enhance antitumor immunity; an orally administered CD40L gene therapy for lymphoma has been tried recently.
|
|
Chronic
lymphocytic leukemia
|
Malignant
cells deliver both CD40 and CD40L, and their interaction may contribute to
tumor growth. This relation supports the
idea that CD40L could be a therapeutic candidate target.
|
|
Hodgkin's
disease
|
The
argument about CD40L survival pathway is build up in patients with B-cell
malignancies
|
|
Pulmonary
fibrosis
|
CD40-CD40L
interaction mediates fibroblast activation and production of the profibrotic
cytokine transforming growth factor. Human lung fibroblasts, from both normal
and scarred lung tissues, can express CD40L; this expression is augmented by
the profibrotic cytokine IL-13 and is downregulated by gamma interferon, which is a
cytokine with anti-scarring property. Fibroblast cell lines from human
idiopathic pulmonary tissues express high levels of CD40L compared to
fibroblasts from non-scarred lung tissues.
|
|
Alzheimer's
disease
|
CD40-CD40L
is critical to the enhancement of microglial cell activation.
|
|
Atherosclerosis
|
CD40
and CD40L are overexpressed in both experimental and human atherosclerotic
lesions. Blocking CD40-CD40L interactions with anti-CD40L MAb in mice can result in diminished formation and progression on mouse atheroma.
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Creative Biolabs is looking for potential partners (including but not limited to major pharma or biotech firms) to develop anti-4-1BB monoclonal antibody program together. Our scientists are dedicated to bringing years of valuable experience to our partner and enabling a meaningful partnership. By doing so, we wish to help both sides to proceed with IND and many stages of clinical trials.
If you are interested, please feel free to contact us so that we can discuss the
program and other possible opportunities for cooperation. Looking forward to working with you in the near
future.
Fig.5 The timeline of Next-IO™ programs.
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