"Left auxiliary right bow" bidirectional VISTA immune checkpoint: immunotherapy to the left, autoimmune disease therapy to the right

summary

The emergence of drug resistance in immune checkpoint therapy highlights the complex variability of tumors and the inadequacy of single-target therapy, and multi-target synergistic therapy has become a better strategy

Recently, Abcam released VISTA EPR21050 clone and Clauddin18.

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Enhanced validation data of histochemical antibodies to other tumor immune targets

Immune checkpoints refer to a class of signaling pathway molecules produced by immune cells that regulate the persistence and immune tolerance of immune responses, and play a role

VISTA (V-domain Ig suppressor of T cell activation, also known as PD-1H, B7-H5, Dies1, Gi24, DD1α) is a noteworthy inhibitory immune checkpoint, which belongs to the B7 family of molecules like CTLA-4 and PD-1/PD-L1, and has a high homology to PD-L1 but has a different mechanism of action, and can be combined

(Left) VISTA deletion reduces the resting phenotype of the initial T cells at the transcriptional and epigenetic levels, resulting in enhancement of the TCR and cytokine pathways disrupting the induction of tolerance to autoantigens and conferring more inflammatory phenotypes

Knocking out the VISTA gene in preclinical studies or blocking VISTA with antibodies greatly upregulates T cell-mediated antineoplastic immunity, resulting in significant expansion of antigen-specific T cells, a stronger response to T cell receptor and cytokine stimulation, and reduced immune tolerance^[1

Human VISTA has been confirmed to have two binding ligands with immunosuppressive functions: VSIG3 and PSGL-1, and one receptor, VSIG8, which has not yet been confirmed ^{[2,4,13,20,21].}

VSIG3 is a member of the Ig superfamily, is homologous to a variety of adhesion receptors, and is known to be expressed in tumor cells such as gastric and hepatocellular carcinoma cells ^[20].

Malignancy and VISTA in immunotherapy

VISTA is widely expressed in myeloid and lymphocytes, especially immune cells in TME

Most models describing effective VISTA treatment rely on a combination approach, possibly because a single blocking VISTA pathway relieves inhibition of the initial T cell, but there are other immune checkpoints that exert inhibitory effects

The combined blockade of VISTA and PD-L1 was optimally treated in two mouse tumor models (CT26 colon cancer cell inoculation and low immunogenic melanoma model^{) [17].}

The potential role of VISTA in autoimmune diseases

VISTA is the key to regulating the T cell immune response to autoantigens, which is obviously an important target for autoimmune diseases
.

Multiple animal experiments have shown that VISTA can inhibit the activation and proliferation of immune cells, reduce the release of inflammatory mediators, alleviate a variety of autoimmune diseases, and can be used as a potential immunotherapy target:

1

VISTA is highly expressed on immune cells with human systemic lupus erythematosus (SLE) lesions
.

Professor Chen Lieping's team reported that knockout OF VISTA in the BALB/c mouse model spontaneously developed skin lesions and systemic autoimmune diseases similar to human lupus; Using VISTA antagonistic antibodies will lead to increased pro-inflammatory responses, accelerated process exacerbations, and shortened survival times in SLE mouse models; Vista agonist antibodies can significantly alleviate skin symptoms and inflammation in SLE mouse models, and reduce the expansion of autoantibodies, inflammatory cytokines, chemokines and immune cells
.

This suggests that VISTA is a key factor in the pathogenesis and progression of lupus, and its activation has the potential to help restore immune balance in systemic patients ^[7,8,9,10].

2

Under both hemipolyolytic and total allogeneic transplantation conditions in mouse GVHD models, single-dose VISTA agonist antibodies can completely prevent GVHD and achieve 100 percent long-term survival in mice ^[24].


When OVA-induced experimental asthma is treated with anti-VISTA agonist antibodies, the number of inflammatory cells in BALF, particularly eosinophils and lymphocytes, as well as lung inflammation and mucus production, can be significantly reduced ^[29].

3

VISTA has an inhibitory effect on the occurrence and development of psoriasis: peripheral tolerance loss on the surface of VISTA knockout mice, spontaneous T cell activation, production of inflammatory cytokines and chemokines, and chronic multi-organ inflammation; VISTA knockout mice showed significantly more severe symptoms in imQ-induced psoriasis models; Healthy mice undergoing IMQ-induced psoriasis after injection of antagonistic VISTA monoclonal antibody also had exacerbated inflammatory symptoms but to a slightly lesser extent than knockout mice, and experiments further confirmed that VISTA plays a key role in inhibiting the IL-23/IL-17-mediated inflammatory axis ^[25].

4

In the mouse model of carnetin A-induced autoimmune hepatitis, VISTA knockout mice had increased sensitivity to induction, overactivation of immune cells in the liver, significantly increased levels of inflammatory factors, and increased mortality, while agonist VISTA monoclonal antibody given before Con A induction was effective in protecting mice, reducing inflammatory levels, and reducing mortality ^[12]

5

In experimental mouse models of autoimmune encephalomyelitis (EAE), knockout of the VISTA gene significantly increased disease morbidity, mortality, and intensity in EAE mice^[11], exacerbating the development of
autoimmune diseases.

These experimental results show from different angles that VISTA is responsible for inhibiting T cell expansion/activation under tolerant conditions, regulating the fate of tolerant endogenous antigen-specific T cells, vista gene deletion can predict a variety of human autoimmune diseases, and VISTA targets have application potential in autoimmune diseases and organ transplantation^[1
].

Drug development for visTA targets is expected to be expected
in both tumor immunotherapy and autoimmune disease therapy.

Clinical drug development at a glance

Drug development targeting VISTA has two different directions
: antagonists and agonists.

Of course, the most concerned is tumor immunotherapy, VISTA antagonists have been small molecule antagonists and monoclonal antibodies into clinical phase I/II research
.

Candidate VISTA antagonist entering clinical trials

Small molecule inhibitors that target VISTA

CA-170 is an oral small molecule peptide double antagonist that selectively targets PD-L1 and VISTA, and is undergoing clinical phase II experiments
as a dual-target inhibitor of PD-L1 and VISTA.

VISTA and PD-L1 have structural similarities, inhibiting T cell function at different stages
.

Preclinical data showed that CA-170 exhibited anti-tumor effects
similar to anti-PD-1 or VISTA antibodies in multiple tumor models.

Ca-170 is acceptable in phase I clinical trials (NCT02812875) at a safe oral dose of 1200 mg BID ^[27].

In 2019, Aurigene published phase IIa clinical data
on CA-170 in the treatment of patients with multiple types of tumors, including head and neck squamous cell carcinoma, nonsquamous non-small cell lung cancer NsNSCLC, MSI-H-positive solid tumors, and Hodgkin lymphoma.

CA-170 showed good safety and efficacy, with an overall clinical benefit rate of 51.
8%, of which the clinical benefit rate of nsNSCLC was >70%, and the data were quite eye-catching ^[27,28].


As the data support ca-170 as promising treatment options for NSNSCLC, in early 2020 Curis announced that a phase IIb/III randomized study was evaluated in approximately 240 patients with NSNSCLC, funded by partner Aurigene and conducted at major cancer treatment centres in India
.

Clinical benefit rates (CBR) in the oral CA-170 400 mg and 800 mg groups in patients with several solid tumors (Source: Curis/Aurigene Phase IIa Clinical Data Report published at the 2019 meeting of the European Society oncology ^[27])

Antagonistic monoclonal antibodies

1

CI-8993 is a VISTA-antagonistic, monoclonal IgG1κ antibody
with active Fc.

Preclinical studies have shown that CI-8993 can increase the number of peripheral tumor-specific T cells and enhance the infiltration, proliferation and effect function of tumor-reactive T cells in TME.
The inhibitory signature of TME can be altered by reducing myeloid immunosuppressive monocytes and granulocytes, increasing the activation of DC cells in TME, and thereby enhancing the T cell-mediated immune response
.

CI-8993 is able to inhibit the growth of transplantable and induced melanoma as a monotherapy ^[28].

CI-8993 (formerly known as JNJ-61610588, VSTB112) was originally developed
by ImmuNext in collaboration with Janssen.

In 2016, Janssen recruited 12 patients in a Phase 1 clinical study evaluating its dose and pharmacokinetics/pharmacodynamics/efficacy in patients with advanced solid tumors, one of whom developed transient dose-limit side effects associated with cytokine release syndrome, and Janssen chose to terminate the study
for "commercial reasons.
"
Curis later obtained the exclusive license from ImmuNext for the development and commercialization of this VISTA monoclonal antibody for cancer
^treatments.

In January 2022, Curis published the results of the PHASE 1 monotherapy study (NCT04475523) of CI-8993 for relapsed or refractory solid tumors, in which 13 patients showed good safety in the 0.
15 mg/kg and 0.
3 mg/kg dose groups (i.
e.
, the dose levels studied before Janssen terminated the program) and no dose-limiting toxicity
was observed.

Pharmacodynamic (PD) effect suggests that CI-8993 may activate multiple anti-cancer immune mechanisms, pharmacokinetic (PK) data suggest that there may be higher bioavailability at higher dose levels, curis is currently recruiting 50 patients with metastatic or unresectable, recurrent and/or refractory malignant solid tumors (non-lymphomas) to determine the maximum tolerated dose (MTD) of full-dose CI-8993, exploring PK/PK/ at higher doses PD relationship (enrollment concentration 0.
6 mg/kg).


Expanded data
is expected to be reported in the second half of 2022.

2

HMBD-002 monoclonal antibody is the first Fc-independent IgG4-type antagonistic anti-VISTA monoclonal antibody
developed by Hummingbird Bioscience.

Interestingly, this antibody was developed with AI guidance and targets a conserved functional epitope on a conserved specific functional epitope
specific to the VISTA-specific C-C' ring.

HMBD-002 monoclonal antibody can block the interaction between VISTA and potential ligands, relieve inhibition of T cell activity, promote TME to anti-tumor phenotypic remodeling in mouse models, and a significant transition to pro-inflammatory phenotype characterized by Th1/Th17 response, and exhibit effective inhibition
of tumor growth in preclinical colorectal, lung and breast cancer models of humanized mouse cancer.

Hummingbird launched a multicenter Phase 1/2 clinical trial (NCT05082610) in October 2021 and is enrolling 240 patients with malignant solid tumors
.

The main clinical goal of phase I is to determine the recommended phase II dose (RP2D)
of HMBD-002 as a single agent as well as a combination of anti-PD-1 monoclonal pembrolizumab in patients with advanced solid malignancies.

The Phase II clinical program will evaluate HMBD-002 alone or in combination with PD-1 monoclonal antibodies in patients with triple-negative breast cancer, non-small cell lung cancer, and other malignancies known to express VISTA ^{[34,35,36,37,38].}

3

W0180 (K01401-020) is a target VISTA monoclonal antibody
developed by pierre Fabre Medical Care's R&D team.

In vitro experiments have shown that W0180 stimulates NK cell proliferation and induces NK cells and monocytes to activate cytokines and promote T cell activation
.

Preclinical studies have shown that W0180 monoclonal antibody infusion therapy in non-human primates can potentially produce a specific CD8+ T cell response against exogenous antigens, effectively enhancing the activity of CD8+ T cells against tumor ^{antigens [13].}


Pierre Fabre launched the Phase I clinical trial (NCT04564417) in September 2020 and is enrolling 69 patients with refractory advanced or metastatic solid tumors with the primary goal of studying the maximum tolerable amount (MTD) and dose limit toxicity (DLTs)
of W0180 monotherapy or in combination with the PD-1 antibody Pembrolizumab.

In June 2022 Pierre Fabre announced that it had commissioned Lonza to produce its W0180 monoclonal antibody
.

4

SG7 monoclonal antibody is an antagonistic VISTA antibody designed by Stanford Researchers using yeast surface display design, which has a high affinity with human and mouse cynomolgus monkey VISTA, and binds to CI-8993 (i.
e.
, VSTB112) competition VISTA, which can block VISTA's interaction with PSGL-1 and VSIG3 proteins and inhibit its function
.

In mouse experiments, SG7 can slow tumor growth (in combination with anti-PD1), inhibit VISTA, and help restore normal T cell activation in a variety of co-lineage mouse models, and can be used as a potential clinical candidate
.

SG7 has not been entered into clinical drug trials ^[2,14].

5

P1-068767 (BMS-767), an antagonistic VISTA monoclonal antibody, is a pH selectively blocking antibody that selectively blocks PSGL-1 interaction with VISTA at pH 6.
0, sufficient to reverse VISTA-mediated immunosuppression
in vivo.

BMS-767 can enter tumor sites at low pH, potentially reducing any non-tumor reactivity and adverse effects
.

BMS-767 is acquired by Bristol-Myers Squibb and has not yet entered the clinical drug trial phase ^[2,4,5,23].

Although at present, according to the domestic clinical drug development trial registration information, there is no VISTA target drug in China that has entered the clinical trial stage, but the official website of Suzhou Stanway Company shows that there is a pre-clinical research and development project for VISTA target antibody drugs, and a number of VISTA antibody patents can be seen in the State Intellectual Property Office, which indirectly indicates the current domestic VISTA target drug development situation: the future is in the ascendant, and the future can be expected
.

As mentioned earlier, most models describing effective VISTA treatments rely on combination approaches, and it is foreseeable that there should be a breakthrough
in the direction of multi-target synergistic therapy in the future around VISTA-targeted drug development.

Agonistic VISTA Target Drug Development: With the popularity of immune checkpoint blockade therapy in the field of cancer, the application of immune checkpoint activation therapy in the field of autoimmune disease treatment and organ transplantation has also begun to receive attention
.

While there are no current records of exciting VISTA target candidates entering clinical trials, a corner of this uncultivated land has been quietly uncovered
.

The potential of VISTA, the only known constitutive type expressed at the immune checkpoint of naïve T cells, responsible for maintaining immune tolerance and immune homeostasis, as a synergistic therapy in the treatment of autoimmune diseases, should be of concern
.

In addition to PD-1/PD-L1 and CTLA-4, more and more immune checkpoints have become a research and development hotspot
.

The LAG-3 inhibitor Relilimab has been approved this year to combine with the PD-1 antibody nivolumab to treat melanoma
in a fixed dose.

In the face of the complex and variability of tumor cells, it is often difficult to "kill one move" in single-soldier combat, and multi-target combination immunotherapy should have a greater chance to benefit
patients.

It remains to be
seen whether VISTA's unique molecular mechanism is clearly different from the already hot immune checkpoints, whether it is safe and effective in combination with other targets in the clinic, and who can make milestone breakthroughs in the new track of VISTA drug development in the future.

epilogue

Abcam provides 3 VISTA recombinant rabbit monoclonal antibodies (RabMAb®), as shown in the table below
.

With its high specificity, sensitivity, and high batch-to-batch stability, Abcam can also develop patented technologies using industry-leading rabbit hybridoma antibodies for the individual needs of pharmaceutical companies/diagnostic companies, providing you with a variety of antibody raw materials
, including VISTA.

Abcam now has a rabbit hybridoma (Hybridoma), B-cell cloning (B-cell cloning), and three rabbit monoclonal antibody (RabMAb®) development platforms based on next-generation sequencing (NGS) technology, which fully meets the various needs of pharmaceutical companies/diagnostic companies, such as diagnostic antibodies (CDx), antibody drug screening and verification antibodies (ADA/PK/PD), and antibody drug precursor discovery (Drug candidate).
discovery) and so on
.

We all look forward to the rabbit monoclonal antibody technology to continue to exert its unique advantages and create new brilliance
.

Working with you for the future
.

Swipe up to view references

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34) A Phase 1 First-in-Human study of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, as a monotherapy and combined with pembrolizumab in patients with advanced solid malignancies.
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