Targeting the Immune Checkpoints for Cancer Immunotherapy

Immune Checkpoint Targets

With something as powerful as the immune system there needs to be restraint. The ability to distinguish between ‘self’, and leave it alone, and the abnormal of foreign, which the body needs to get rid of.

‘Immune checkpoints’ are the parts of immune pathways where molecules need to be either activated or deactivated for an immune response to progress. They help the immune system to learn what to become tolerant to and what to attack.

The normal system for immune checkpoints can be disrupted or derailed. Cancer cells can exploit checkpoints allowing them to remain hidden from, and unpunished by, the immune system.

However, by better understanding immune checkpoints and how tumours exploit them we can develop new drugs that also target these pathways, drugs that correct the errors.

This is the bases of a growing area of research and a number of new cancer immunotherapies.

Working with our partners, including BioXCell, AcroBio Systems, Cusabio, Elabscience and BT-Labs,  2BScientific is proud to be able to offer a wide range of products for investigation of immune checkpoints, including antibodies, proteins and ELISAs.

 

CTLA-4 (CD152):

CTLA-4 is found only on T-cells and, at its simplest, can be thought of as an ‘off’ switch for activated T-cells. It tells the T-cell that even though there is an antigen, ignore it – become tolerant to it.

Fig 1. Crystal structure of CTLA4

 

A T-cell needs two complimentary signals to become activated. The T-cell receptor must be engaged by an antigen alongside a secondary signal from either soluble proteins (e.g. IL-2) or cell-surface molecules on an antigen presenting cell. Following activation, the T-cell response can be either amplified, via CD28, or downregulated by CTLA-4.

CD28 and CTLA-4 both share the same ligands, B7.1 (CD80) and B&.1 (CD86). Current thinking in how these two molecules vie for control over the T-cell is that CTLA-4, if present, has a much higher affinity than CD28 for the two ligands and thus out competes CD28 for them and control of the T-cell response.

Its role is as a checkpoint for T-cell activation.  If CTLA-4 is activated it down-regulates the T-cell and inhibit its expansion.

In normal situations, this CTLA-4 ‘checkpoint’ promoting self-tolerance and preventing the body from launching inappropriate autoimmune responses. However, some tumour cells have been found to co-opt this process, allowing them to evade attacking T-cells, even though the immune system recognises tumour antigens which are, otherwise, non-self. 

CTLA-4 was the first immune checkpoint receptor to be targeted as a potential treatment for some cancer. Blocking of CTLA-4 using antibodies removes the checkpoint, allowing the immune system to continue to attack these tumour cells, and is the basis of CTLA-4 blockade as a cancer immunotherapy.

Fig 1. InVivoMAb anti-mouse CTLA-4 (CD152) (BioXCell Cat# BE0164)

The first (humanised) CTLA-4blocking antibodies used for this were ipilimumab and tremelimumab.

 

2BScientific CTLA-4 product range:

Recombinant CTLA-4

CTLA-4 Antibodies (including neutralising/blocking)

CTLA-4 ELISAs
 

Programmed Cell Death Protein 1 - PD1 (CD279) and PD-L1:

PD1, like CTLA-4, is a cell surface receptor found on activated T-cells.  Where CTLA-4 regulates the activation of a T-cell, PD1 regulates a T-cell’s effector activity (post-activation) – a second checkpoint, as it were, that limits the development of a T-cell response.

Two known ligands for PD1 exists: PD-L1 (B&-H1/CD274) and PDL2 (B7-DC/CD273). Binding of PD-L1 to PD1 results in halted or reduced cytokine production and suppressed T-cell proliferation.

In contrast to CTLA-4, where the mechanism by which a tumour cell co-ops the CTLA-4 pathway remains somewhat unclear, the process for PD1 is much less murky. Tumour cells in the periphery begin to over-express PD-L1 on their surface. This is done either constitutively, i.e. tumour cells permanently expressing PD-1L, or its expression is induced in response to inflammatory signals (typically IFN-gamma).

As with CTLA-4, blockade of the PD1 receptor is one pathway to cancer immunotherapy, while blockade of the PD-L1 ligand is the other.

Pembrolizumab and nivolumab are both PD1 blocking antibodies in clinical use, while atezolizumab is a PD-1L blocking antibody in clinical use.

Fig 2. The purity of Human PD-L1 From ACRO Biosystems (Cat# PD1-H5229) was >95% as determined by SEC-HPLC and >98% as determined by SDS-PAGE.

 

 

Fig 3. InVivoMAb anti-mouse PD-1 (CD279) (BioXCell Cat# BE0146)

 

2BScientific PD-1 product range:

PD-1 Antibodies (including neutralising/blocking)

PD-1L Antibodies

PD-1 proteins

PD-1L proteins

PD-1 ELISAs/kits

PD-L1 ELISAs/kits
 

Providing academic discounts across numerous suppliers and products including BioXCell, please contact us today for more details.