Perspectives in the Future Development of Molecular Pharmacology: Vaccines and Recombinant Antibodies

Perspectives in the Future Development of Molecular Pharmacology: Vaccines and Recombinant Antibodies

Possani, Lourival

Professor of the Biotechnology Institute, National Autonomous University of Mexico, Avenida Universidad, 2001, Apartado Postal 510-3, Cuernavaca, Morelos 62210 México

In a previous meeting of our study group, we discussed the trinomial: Science-Industry-Medicine. We anticipated the impossibility of attaining a suitable development in modern molecular pharmacology, unless strong interaction and tight communication is established between investigators studying the structure and function of the informational biomolecules (nucleic acids and proteins), with the industry that produces chemicals based on the scientific findings, and medical doctors that prescribe such chemicals or pharmaceutical products. During the last meeting in Acapulco, we revised the basic state-of-art knowledge on the biochemical and functional organization of living cells, indicating the direction in which we thought focus and attention should be concentrated in order to provide adequate and efficient intervention in the treatment of animal envenomings. We discussed that envenomings due to venomous organisms and the possible control of the biological dysfunction caused by their toxins in humans demand first that the chemical nature of the toxic agent of the venom is known, and that the receptor molecule that receives its action is accurately determined. It is necessary to know which toxic agent causes tissue damage or lethality to the affected organism. The knowledge of toxic biomolecules and their targets in the recipient organism is the first step towards rationally designing antidotes and vaccination procedures for the prevention of disease or possible deaths by microorganism, plant, and animal envenomings.

On this occasion, we wanted to comment on the most plausible future perspectives that are likely to be considered at the beginning of the new millennium in the development and usage of an intelligently applied molecular pharmacology.

1. Efforts will continue aimed to the development of new vaccines based on chemical synthesis of peptides, corresponding to the immunological competent epitopes or the active sites of both toxins and neutralizing antibodies.

2. Emphasis will be given to the search for new analogues of toxins to insects and crustaceans, capable of presenting cross-reaction with toxins non-toxic to mammals. That is, structurally similar peptides toxic to arthropods will be used for human vaccination, because they are not toxic to mammals.

3. By genetic engineering proteins and nucleic acids, novel vaccines and therapeutic fragments of antibodies (Fab-therapics) will be developed, including the use of antibody libraries or phage-display libraries for obtaining better antibodies or tailoring fragments of antibodies capable of neutralizing the effect of toxins.

4. Increasing usage of the nuclear magnetic resonance (NMR) and X-ray diffraction crystallographic techniques will allow the determination of the three-dimensional structure of toxins and their target molecules.

5. More attention will be given to finding new venom components, with possible applications in the development of new drugs: specific ligands for certain types of receptors and/or new antibiotics.

6. Finally, new techniques will be implemented and new diagnostic kits will be developed to help physicians in the treatment envenomings.

Two concrete examples will be shown to illustrate the above: 1) to obtain a recombinant vaccine against the spider Latrodectus mactans venom, commonly known as "black-widow spider" (patent deposited in Mexico, No. 9911191, Dic.1999); 2) a monoclonal antibody raised against Cn 2, a major toxic component of the scorpion Centruroides noxius venom. This is the scorpion with the most potent venom known in the Mexican Republic, since its LD50 in mice is 5 micrograms per 20 grams body weight. Several murine monoclonal antibodies were obtained against toxins from this scorpion venom, from which the BCF2 antibody capable of neutralizing the action of Cn 2. This antibody not only neutralizes the action of the pure toxin, but also the whole venom. The three-dimensional structure of Cn 2 was determined by NMR and the putative active site of the toxin was determined by synthetic peptides. A model of the three-dimensional structure of the variable region of BCF2 was built, based on similar known antibodies. The knowledge of the three-dimensional structure of Cn 2 and of the active site of Cn 2 allowed the design of a complex three-dimensional model showing the interaction of Cn 2 with the BCF2 fragment.

This type of studies opens the possibility for the rational design of potential vaccines or the development of humanized antibodies and/or modified antibodies to be used as novel pharmaceutical products, that is, to be used as Fab-therapics of fourth and fifth generations.

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Publication Dates

• Publication in this collection
  08 Oct 2002
• Date of issue
  Dec 2001