Author: Shabbir Chunawalla

The therapeutic agents mostly act by interacting with a biological macro-molecule, say by activation of a receptor or inhibition of an enzyme or inter-calating into the DNA etc. These interactions can be understood by examining the 3D structures of the drug. The structural analysis of the drug-receptor complex can be appreciated if the macro-molecule is seen in pure crystalline form, but such crystallisation of most receptors is difficult. It is in this context that models of the receptors and their complexes with ligand are constructed by molecular modelling. It is a computer-based method. In its simplest form, it involves converting each atomic coordinate into a corresponding screen coordinate and then connecting the appropriate atoms by lines representing bonds. Most molecular modelling studies start with the selection of a model that describes the intra- and inter-molecular interactions in the system. The two most common models that are used are quantum mechanical and molecular mechanics. Molecular mechanics treat each atom as a ball of mass proportional to its atomic weight. Each bond is treated as an analog of a mechanical spring. The total potential energy of the molecule is computed by assessing the bond stretching, angle bending and torsional motions. In quantum mechanical approach, the quantized wave-like behaviour of the electrons and the nuclei is assessed.

IITs too realise that they must step up their efforts in R&D. R&D does need huge funding. The premiere institutions are considering corporate funded science parks and research centres which would be state-of-the-art.

IITB will have a research park on its campus. It is setting up a company (NPO) to manage and govern this park. IITM has already built a reserch park, and is considering a second one. IITD would like to set up research centres in Haryana. IITK has its research complex on the campus. IIT-Kharagpur will have a cenre in Kolkata.

The concept is to bridge the academia and the outside world.

R & D costs of big pharma companies are inflated. The one billion dollar figure as the cost of drug discovery started floating ever since The Tufts Centre for the Study of Drug Development, Boston study in 2000. The study took inflated figures of patients per drug trial. It added cost of capital to the drug discovery cost where capital cost is defined as the money the company would have made, had it invested in the stock market instead of R & D. It assumed a hypothetical return of 11 per cent compounded over 7-5 years ( the period to complete clinical trials and get the approval from the FDA ). It should have considered a realistic return of  3-7 per cent. The trial and approval period could have been reduced to 4 years. The tax subsidy enjoyed by the companies on R & D  expenditure is not included in the cost. The marketing spends which include freebies to doctors and sponsorships for conferences are much higher. Besides a few drugs are really innovative, some are modified versions and most are me-too products. The industry claims high costs for each and every drug brought into the market. Even if we assume the inflated figure of one billion dollar for drug discovery, companies earn many times that amount in a year. There is an average 19% profitability, almost on par with oil industry’s profitability.

As most cancer drugs are cytotoxic, they not only act on cancer cells but also on normal cells. In other words they are not selective. Vaccines which are threpeutic and act only on cancer cells are the way out. These have reached the phase III of Clinical trials. These are designed by several ways — from dendritic cells, irradiated tumour cells mixed with BCG, tumour-derived heat shock protein peptide complex.

Denaritic cell-based caccines stimulate dendritic cells ( DC ) of the patient ex vivo ( through exposure to tumour cell lysate ) to fuse with tumour cells ( virus-infected ). These are given back to patients to initiate antigens to the T cells in the effector arm of the immune system.

Irradiated tumour cells of the patient has no harmful factor in the cells. These are mixed with BCG vaccine.

Heat shock protein peptide complex are found in all cells. They act as chaperones. They carry while transporting a large reportoire of proteins and peptides. HSPs are complexed with antigenic peptides to generate immune response. These are highly useful in fibrosarcoma, leukaemia, melanoma, and lung, colon, breast and prostate cancer.

Products under clinical trials

• OncoVAX has derived cells from the excised tumour which are mixed with BCG to boost patient’s immune res response.
• Oncophase ( Vitespen ) uses HSPs and peptides derived from patient’s tumour cells.This comprises a sort of antigenic fingerprint — unique to each patient’s cancer.
• Provenge ( Sipuleucel-T ) is autologous ( patient derived DC that have been cultured with a delivery cassette that contains a version of prostate-cancer associated version of Prostatic Acid Phosphatase (PAP ) and the cytokine granulocyte-macrophase colony-stimulating factor ( GM-CSF ). It is designed to activate specialised immune cells called T cells to recognise and destroy cells bearing PAP antigen. Here patient’s own tumour is not used to initiate antigenic response but a generic antigen is used common in prostate carcinoma.

Favid uses patient-specific idio-type protein isolated from tumour biopsy. It is conjugated with keyhole limpet hemocyanin ( KLH ). This is useful in non-Hodgkin’s lymphoma.

MyVax is patient-specfic idiotype conjugated to KLH.

Stimuvax is non-patient specific vaccine. It has a synthetic peptide derived from tumour associated antigen MUC 1.

GSK 1572932A is non-patient specific consisting of a purified recombinant MAGE- A3 protein.

Vaccines are used as adjuvants or in earlier-stage disease. They are yet to be tested on larger populations.

Newer vaccines include synthetic, recombinant or highly purified subunit antigens that are weakly immunogenic. Therefore, these formulations require adjuvants for better immunologic efficiency. Immuno-modulators obtained from different sources such as synthetic, bacterial and viral have been used for enhancement of immune response to vaccines. Plant-based products are being considered as one option for immune adjuvants.

A new patent has been granted in the US for a vaccine adjuvant extracted from Ashwagandha (Withania somnifera ). It is used in Ayurveda as immunity enhancer. Researchers are also examining the immuno-modulatory activity of medicinal plants such as Shatavari and Guduchi.

The new adjuvant can be applied in ailmants like meningitis, diphtheria and tetanus among others.