Lymphocyte Activation - Therapeutic Agents

Question 1

What is the goal of therapeutic agents that affect T cel activation?

Answer 1

To inhibit the immune response

Used to treat autoimmunity or to prevent rejection in transplantation

Question 2

List some examples of therapeutic agents that affect different aspects of the T cell activation process
(4)

Answer 2

Belatacept (Nulojix) -> for autoimmune and anti-rejection

Ipilimumab -> for cancer

Nivolumab -> cancer

Durvalumab -> cancer

Question 3

How does Belatocept work?

Answer 3

It works by mimicing the function of CTLA-4 and thus stopping the co-stimuatory signal of T cell activation

Question 4

What is the structure of Belatoecpt?
(3)

Answer 4

A chimeric molecule that resembles an Ig, it is called CTLA-4 Ig

The ‘Fab’ part is essentially a modified CTLA4 with increased avidity for B7 binding -> stronger binding than wild type CTLA4 to B7

It has an IgG1 domain which resembles an Fc portion of an Ig which is responsible for slowing down the clearance of the molecule from circulation (it is essentially the tail of IgG1 added on)

Question 5

What is Belatocept used for?
(2)

Answer 5

Its used to switch off unwanted immune responses

Particularly useful in psoriasis vulgaris treatment

Question 6

What affects did Belatacept have on psoriasis patients?

Answer 6

43 patients studied

46% experienced a 50% or > sustained improvement in their skin condition

Dramatic improvement due to switching off of T cell activity through competition with the autoimmune response

Question 7

How did Belatocept work to improve psoriasis symptoms in patients?
(2)

Answer 7

Psoriasis is autoimmune i.e. caused by unwanted T cell activation

Belatocept CTLA4-Ig competitively bound to B7 preventing binding to CD28 and thus preventing cascade

Question 8

What is currently the go-to anti-rejection drug for renal transplant patients, why are we looking to replace these?

Answer 8

Calcineurin inhibitors such as cyclosporin A

Want to find a safer alternative so that we can maintain effective long-term immunosuppression with less toxicity

Question 9

Why hasnt Belatacept replaced cyclosoprin A as an anti-rejection drug?
(3)

Answer 9

Belatacept has shown great promise in clinical trials but has made halting progress towards replacing CNIs in actual clinical practice

Belatacept-treated patients experienced higher acute rejection rates and greater risk for PTLD (EBV)

Belatacept also requires monthly intravenous infusions that have presented with logistical and cost challenges for widespread adoption

Question 10

What are the benefits of Belatacept over cyclosporin A as an anti-rejection drug, even though Belatacept is not to be used as such?
(2)

Answer 10

Belatacept maintained renal function after transplants

It reduced some of the metabolic side affects seen with calcineurin inhibitors such as cyclosporin A related to hypertension and dyslipidemia

Question 11

How is Belatacept monitored?

Answer 11

Belatacept binding is monitored by flow cytometry

Its therapeutic efficacy is assessed by measuring the relative frequencies of cellular subsets e.g. CTLA4-B7 binding vs CTLA4-Ig - B7 binding

Question 12

What does ipilimumab do?

Answer 12

Ipilimumab blocks negative signalling from CTLA-4

Question 13

When would we need to block the negative signalling from CTLA-4 i.e. when would we need to kill cells which have sent out a block signal?
(2)

Answer 13

In cancer, cancer cells can protect themselves from cell death by blocking T cell mechanisms through CTLA4

Ipilimumab can turn off this inhibitory mechanism of CTLA4 to allow the CTLs to continue to destroy the cancer cells

This leaves B7 free to bind CD28 and thus attack cancer cells

Question 14

What is the molecular name for Ipilimumab?

Answer 14

alpha-CTLA-4

anti-CTLA-4

Question 15

What is PD-1, where is it found, what does it bind?

Answer 15

Its an inhibitory receptor of the CD28 family

It is found on T cells, B cells and monocytes upon activation

It has two ligands which are homologous to B71 and B72:
- PD-L1
- PD-L2

Question 16

How does PD-1 binding stop T cell activation?
(3)

Answer 16

There is an ITIM and an ITSM region in the cytoplasmic tail of PD-1

These regions recruit SHP-1 and SHP-2 (tyrosine phosphatases)

SHP-2 dephosphorylates the tyrosine residues of the ITAMS of CD3 -> resulting in a closed/inactive CD3 and thus stopping cell activation

Question 17

What are ITIMS and ITSMS

Answer 17

Immunoreceptor tyrosine-based inhibitory motif

Immunoreceptor trosine based swith motif

Question 18

How can cancer take advantage of PD-1?
(3)

Answer 18

Cancer cells can inhibit the work of T cells by binding to PD1 on the surface of T cells

Cancer cells can do this by expressing PD-L1 on their surface

PD1 binding -> dephosphorylation of ITAMS in CD3

Question 19

Give an example of an anti-PD1 drug?

Answer 19

Nivolumab (anti-PD1) and Durvalumab (anti-PDL1) drug

Question 20

Explain how anti-PD1 therapies work

Answer 20

Two methods used:

Nivolumab (anti-PD1) -> antibody that binds to PD1 on T cells to block inhibitory signal of PDL1 from binding

Durvalumab (anti-PDL1) -> antibody that binds to PDL-1 on cancer cells stopping binding to PD1 on T cells

Question 21

Nivolumab is an anti-PD1 antibody, what is another antibody therapy with the same function?

Answer 21

Pembrolizuman
(Keytruda)

Question 22

Durvalumab is an anti-PDL1 antibody, what is another antibody therapy with the same function?

Answer 22

Avelumab

Question 23

Give another example of CTLA-4 inhibitors other than ipilimumab

Answer 23

Tremelimumab

Question 24

Mention a little on Talquetamab

Answer 24

A monocloal antibody treatment made in Cork

Its bimolecular i.e. has two targets: targets CD3 and protein expressed on myeloma cells (GPRC5D protein)

It bridges these two molecules bringing the myeloma cells closer to the CD3+ cytotoxic T cells

Really promising in patients so far