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Antitumor peptide immune checkpoint inhibitors

 Last Update: 2022-11-15
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Source: Yaodu

Written by: Ko Ha Ji Editor: Maruko

The FDA has approved AstraZeneca's Imjudo (tremelimumab) combined with Imfinzi (durvalumab) dual immunomodulator therapy for the treatment of hepatocellular carcinoma, which is the second time this year that the FDA has approved dual immunotherapy for the treatment
of tumors.
On March 18, Bristol-Myers Squibb's Opdualag^TM (nivolumab and relatlimab-rmbw) was approved by the FDA for the treatment of unresectable or metastatic melanoma melanoma)
。
Antibodies are undoubtedly the main force of immunotherapy for the treatment of tumors, including dual immunotherapy, however, antibodies have disadvantages
such as high cost and poor oral applicability.
Peptide drugs, which are much smaller than the molecular weight of antibodies, also play a non-negligible role
in the treatment of immunotherapy against tumors.

Because of their small size, high affinity, easy modification, and low immunogenicity, peptides have also attracted much attention
in the field of tumor diagnosis and treatment.
Some modified peptides show good stability
.
, such as the antibody proteins
in two dual immunomodulators approved by the FDA this year.
Peptide molecules can act as immune checkpoint inhibitors in tumor immunotherapy.

Instead of directly attacking tumor cells, immunotherapy drugs modulate the patient's own immune system and attack tumor cells
by targeting immune checkpoints.

Immune checkpoints and

Immune checkpoint inhibitors

1Immune checkpoints

Immune checkpoints come into play
when proteins on the surface of immune cell T cells recognize and bind to chaperone proteins on other cells, such as some tumor cells.
The proteins on these T cells are called immune checkpoints
.
When checkpoints bind to the cancer cell's chaperone protein, they send a "off" signal
to the T cell.
Immune checkpoint molecules play a key role in the immune escape of tumors, and clinically can restore the anti-tumor function of immune cells by blocking the binding of immune checkpoints and ligands, so as to achieve the purpose of
treating tumors.

2Immune checkpoint inhibitors

Since immune checkpoints help prevent the immune response from being too strong and can sometimes prevent T cells from killing cancer cells, when these checkpoints are blocked (suppressed), T cells can better kill cancer cells, which undoubtedly has a very positive effect on
tumor treatment.
Immune checkpoints are targets for cancer immunotherapy because they have the potential to be used to treat
many types of cancer.
Currently approved checkpoint inhibitors block CTLA4 and PD-1 and PD-L1
.

Peptide immune checkpoint inhibitors

1CTLA4 inhibitors

CTLA-4 or CTLA4 (cytotoxic T lymphocyte-associated protein 4), also known as CD152, is a protein receptor that acts as an immune checkpoint and downregulates the immune response
.
CTLA-4 is expressed in regulatory T cells, but is upregulated in regular T cells only after activation, especially in cancer
.

The mAb antibody inhibitor against the immune checkpoint CLTA4 is Ipilimumab
, which treats melanoma.
Many active peptides also showed good inhibition of CTLA4, such as yeast display peptide ERY2-4 (Figure 1) specifically binding to CTLA-4 with a KD of 196.
8 ± 2.
3 nM
.
Furthermore, ERY2-4 blocks the interaction
between CTLA-4 and dendritic cells (DCs) that present B7 on their surface.
Importantly, ERY2-4 did not show cross-reactivity against CD28, indicating that it does not inhibit T cell activation
.
Because CTLA-4 is a critical immune checkpoint that limits the cancer immune response, this inhibitory peptide represents a new class of immunotherapy
candidates.
Figure 1.
Yeast shows the chemical structure of
the peptide ERY2-4.

2PD-1

Although PD-1 and CTLA-4 belong to the CD-28 immune checkpoint receptor family, their role in suppressing the immune response is mechanically different
.
CTLA-4 regulates the immune response mainly in the lymph nodes in the early stages, while PD-1 regulates immunosuppression
mainly in peripheral tissues in the later stages.
Although clinically approved antibodies against both pathways produced long-lasting clinical responses, they both led to adverse events, with a higher
incidence of anti-CTLA-4 antibodies and higher levels of immune-related adverse effects.
The better clinical profile of PD-1/PD-L1 checkpoint inhibitors in terms of efficacy and safety has led to rapid drug development and approval
in multiple indications.
In this area, Bristol-Myers Squibb patented their cyclic peptides, showing nanomolar activity
in inhibiting PD-1/PD-L1 interactions.
Figure 2.
WO2017176608 patented peptide, PD-1/PD-L1 and CD80/PD-L1 protein binding inhibitor
.

3BTLA-4

B and T lymphocyte attenuating factor (BTLA) is another co-inhibitory receptor
in the CD-28 family.
In a recent report, based on the natural protein HVEM (herpesvirus entry mediator) bound to BTLA, researchers designed a disulfide bridging peptide using HVEM (14-39) fragments (Figure 3) and demonstrated its cellular viability
using BTLA-expressing 293T cells.
HVEM (14–39) peptides are inhibitors of BTLA/HVEM binding and inhibit the formation
of BTLA/HVEM complexes in a dose-dependent manner.
It has development value
in the field of immunotherapy against tumors.
Figure 3.
HVEM (14-39) peptide molecular structure
.

4VISTA

VISTA is an immune checkpoint in the B7 family that co-regulates T cell responses
with the PD-1 protein.
CTLA-4 and PD-1 inhibit immune function during the T cell initiation and effector phases, while VISTA suppresses the immune response
during the earliest stages of T cell activation.
For this reason, the researchers designed the VISTA peptide antagonist.

This is a cyclic peptide containing a disulfide bond and multiple D-amino acid residues (Figure 4).

Figure 4.
VISTA peptide inhibitors
.

This peptide VISTA antagonist significantly enhances T cell proliferation
compared to anti-VISTA antibodies or anti-PD-L1 antibodies.
In addition, the antitumor efficacy of this VISTA antagonist peptide was demonstrated
in a model of immunogenic bladder cancer MB49.
The authors note that the mechanism of action may be that the peptide binds to the key/active site of VISTA, thereby blocking the immunosuppressive function
of VISTA.

5LAG-3

LAG-3 is the third clinically targeted immune checkpoint receptor
after CTLA-4 and PD-1.
LAG-3 co-expresses with other receptors, especially PD-1, and inhibits immune function in a variety of environments, making it an attractive target in combination with PD-1
.
Combination therapy with anti-LAG-3 and anti-PD-1 antibodies has been successful
in melanoma.
Bristol-Myers Squibb's OpdualagTM was approved by the FDA on March 18, 2022, and its active ingredients nivolumab and relatlimab-rmbw are antagonists
of PD-1 and LAG-3, respectively.
OpdualagTM became the first immunotherapy
approved by the FDA to target LAG-3.

In the study of the peptide class of LAG-3 antagonists, the researchers designed a disulfide-linked cyclic peptide named C25 (Figure 5), which has a KD value on the mM order and can effectively bind to LAG-3, thereby effectively interfering with the binding
between LAG-3 and MHC-II (major histocompatibility complex protein II).

Figure 5.
LAG-3 antagonist C25 chemical structure

summary

Immune checkpoint antagonists are currently antibody-based, but low response rates and immune-related adverse events require the development of more effective and safer treatments
.
Peptide drugs offer potential advantages
in selectivity, efficacy and reduced off-target toxicity.
Peptide immunotherapy may create a situation in the future that goes hand in hand with antibody drugs, and there may also be a peptide dual immunotherapy
similar to OpdualagTM.

[1] Syn, N.
L.
et al.
De-novo and acquired resistance to immune checkpoint targeting.
The Lancet.
Oncology.
2017, 18, e731–e741.

[2] Tharanga, M.
R.
et al.
An Immune-Stimulatory Helix–Loop–Helix Peptide: Selective Inhibition of CTLA-4–B7 Interaction.
ACS Chem.
Biol.
2020,15, 360–368.

[3] S.
C.
Wei, S.
C.
et al.
Fundamental mechanisms of immune checkpoint blockade therapy.
Cancer Discov, 2018, 8, 1069-1086.

[4] Callahan, M.
K.
At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy.
J Leukoc Biol, 2013, 94, 41-53.

[5] Vaddepally, R.
K.
Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence.
Cancers.
2020, 12, 738.

[6] WO2017176608 - Macrocyclic inhibitors of the pd-1/pd-l1 and cd80/pd-l1 protein/protein interactions.

[7] Spodzieja, M.
et al.
Disulfide-linked peptides for blocking BTLA/HVEM binding.
Int.
J.
Mol.
Sci.
2020, 21, 636.

[8] Liu, J.
et al.
Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses.
Proc.
Natl.
Acad.
Sci.
U.
S.
A.
2015, 112, 6682-6687.

[9] Randolph, J.
et al.
Vista antagonist and methods of use.
WO2015109340A2.

[10] Zhai, W.
et al.
A novel cyclic peptide targeting LAG-3 for cancer immunotherapy by activating antigen-specific CD8+ T cell responses.
Acta Pharm Sin B, 2020, 10, 1047-1060.

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