Please READ THE INFORMATION IN THE QUESTION CAREFULLY before answering.

1.       Answer ALL parts of this question.

a)       Both   pembrolizumab   and  durvalumab  are  monoclonal  antibodies  for  the treatment of cancer. Pembrolizumab is a PD-1 inhibitor whereas durvalumab is a PD-L1 inhibitor, both are immune checkpoint inhibitors.

(i)       Compare and contrast pembrolizumab and durvalumab in terms of their target sites, mechanism of action and toxicity profile.                  (30% of marks)

(ii)       Is it feasible to develop a single-chain variable fragment (scFv) that targets PD- L1 as a treatment of cancer? Explain your answer with reference to the structure of scFv.                 (20% of marks)

b)       Vascular endothelial growth factor (VEGF) is another target for antibodies for the treatment of cancer.

(i)       “Anti-VEGF antibodies are effective against solid tumours but not leukaemias or lymphomas”. Is this true? Explain your answer.    (30% of marks)

(ii)      Anti-VEGF  antibodies  can also  be used in the treatment of wet age-related macular degeneration (AMD). Is it feasible to develop a nanobody that targets VEGF for this condition? Explain your answer with reference to the structure of a nanobody. (20% of marks)

2.       Answer ALL parts of this question.

a)       Compare and contrast the expression of recombinant proteins using E. coli and Chinese Hamster Ovary (CHO) cells.        (30% of marks)

b)       What  causes  protein  to  aggregate? What are the  potential consequences of administrating aggregated protein therapeutics? Discuss.           (30% of marks)

c)       What is a biosimilar product? Discuss the different goals in the development of a new biologic therapeutic and a biosimilar product.                       (40% of marks)

3.       Answer ALL parts of this question.

You are working as a formulation scientist in a pharmaceutical company. Your colleagues are developing a small interfering RNA (siRNA) for the treatment of lung cancer by targeting the epidermal growth factor receptor (EGFR) which plays a  critical  role  in  the  proliferation  and  progression  of  various  cancers including lung cancer.

a)       Explain the general principle of how siRNA can be used as therapeutics. (30% of marks)

b)       Your colleagues ask you to develop a delivery system for this siRNA. They want to employ a delivery platform that has already been used clinically - either GalNAc-siRNA conjugates or lipid nanoparticles (LNPs). Which platform is more suitable for use in the treatment of lung cancer?  Explain your answer with reference to the principle of both delivery platforms. (70% of marks)

4.       Answer ALL parts of this question.

A company is developing a vaccine to a new viral pathogen named KC3. The pathogen is known to be highly dangerous (mortality rate of > 30% of infected individuals), to have a large number of serotypes, but to mutate slowly. It is found that there area number of surface proteins on KC3: P1 plays a major role in cellular uptake but is not conserved across serotypes, whereas P2 and P3 do not affect uptake but are found to be highly conserved across serotypes. The company has access to a wide suite of technologies for molecular biology, and has secured a supply of the alum adjuvant from a well-respected supplier.

a)       What type of vaccine would you recommend that the company focus on? Explain your answer. (70% of marks)

b)       Consider the properties of the three surface proteins P1, P2 and P3. Which do you think would be the most suitable target for a vaccine? (30% of marks)