PH3113 Unit 2 Immune checkpoint inhibitors

What type of drugs are the current immune checkpoint inhbitors?

Monoclonal antibodies - IgGs

All human (-umab) or humanised (-zumab)

Why are monoclonal Ab better than polyclonal?

Polyclonal have a higher chance of showing cross-reactivity and causing off-target effects

Why are human Abs preferred to murine?

As lower risk of immunogenicity

What determines the half life of IgGs? What is it approximately? How is it protected?

The Fc region determines half-life

Full length IgGs have 21 days (3 weeks) half-life, while Ab fragments are only a few hours

FcRn (neonatal fragment crystallizable receptor) expression on capillary vasculature protects IgGs from lysosomal degradation

What type of inhibitors are all approved ICIs?

Protein-protein interaction inhibitors

How is CTLA-4 targeted by ICIs?

An anti-CTLA-4 antibody (ICI) blocks binding of CTLA-4 to B7-1/2 → activating T cells → kill tumour cells

Binding of CD80 (B7-1) or CD86 (B7-2) to CTLA-4 keeps T cells in inactive state = do not kill tumour cells

How are anti-CTLA-4 monoclonal Abs administered?

IV infusion administration either monotherapy of combination

How is PD-1 targeted by ICIs?

PD-1 is a surface receptor expressed on activated T cells, B cells and NK cells.

It binds to its ligands: PD-L1 and PD-L2 to transmit a co-inhibitory signal → preventing T cell activation → do not kill tumour cells

Blocking PD-L1 with ICIs of anti-PD-L1 or anti-PD-1 → T cell activation → kill tumour cells

Are anti-PD-L1 or anti-PD-1 more selective? Why?

PD-L1 inhibitors are more selective for cancer cells as it is overexpressed in some cancers.

They do not affect the PD-1/PD-L2 interaction.

PD-1 inhibitors block both PD-L1 and PD-L2.

PD-L2 is found on APCs.

What are 5 disadvantages of monoclonal Ab use?

Limited tissue and tumour penetration due to high MW

Long half-life

Poor/no oral bioavailability so disadvantages of IV administration (phobias, hospital/nurse administration)

Immunogenicity

Higher production costs

What is a target of current non-ab alternative inhibitors? What are the 3 types molecules?

Alternative PD-1/PD-L1 interaction inhibitors

Peptides, Peptide mimics, Small molecule agents

How can macrocyclic peptide mimics target PD-1/PD-L1 interaction?

Mimic key antibody residues that interact at interface between PD-1 and PD-L1 to antagonise signalling → activating T-cells → kill tumour cells

How can small molecule protein-protein interaction inhibitors target PD-1/PD-L1 interaction?

Bind to PD-L1 at interaction site to block interaction with PD-1 → active T-cells → kill tumour cells

What are ADRs of monoclonal antibodies? Common and rare but potentially fatal? Why?

Can cause uncontrolled immune system activation to cause immune-related adverse events (similar manifestation to autoimmune disorders)

Common: fatigue, GI (NVD), endocrine toxicity, dermatological toxicity

Rare but life-threatening: neurotoxicity, cardiotoxicity, pulmonary toxicity

Do CTLA-4 inhibitors or PD-1/PD-L1 inhibitors have a greater risk of immune-related adverse events?

PD-1/PD-L1 tend to be less severe (mainly fatigue) as they have greater antitumour activity, higher selectivity for immune suppressive signals delivered by tumour as PD-L1 is overexpressed in tumour cells

CTLA-4 can be on all T-cells, no specific tumour target

Why do only some patients respond to CTLA-4 or PD-1/PD-L1 blockade?

Due to primary and acquired resistance

What are some additional targets being investigated for having less immunological tolerance? aka used to enhance ICIs

LAG-3 and TIM-3

How does targeting LAG-3 help against immunological tolerance?

LAG-3 is expressed on activated T cells, NK, B, and DCs

It interacts with MHC class II to inhibit cytotoxic T-cell activation → preventing autoimmunity

T cells in tumour microenvironment overexpress LAG-3

Blocking LAG-3 favours immune activation against cancer cells, enhancing effects of other ICIs

How does targeting TIM-3 help against immunological tolerance?

TIM-3 stimulation promotes immune tolerance → favours T cell exhaustion → facilitating tumour growth

aka high TIM-3 = poorer prognosis

Blocking TIM-3 → favours immune activation against tumour cells → enhancing effects of other ICIs