[Cationization, a process for the delivery of antibodies to the central nervous system. Problems encountered in its application for immunotherapy strategies such as those for clostridial poisoning].
The central nervous system is separated from the rest of the body by the blood-brain barrier. This barrier prevents many substances, such as the antibodies, to penetrate into the brain making it difficult to use them for the treatment of brain diseases, such as tetanus and botulism. These two diseases are caused by the development of bacilli of the genus Clostridium which release neurotropic toxins. Specific antibodies can neutralize toxin activity when the toxin is in the blood but are ineffective when it is transported into nerve cells. Various invasive strategies have been used to deliver antibodies to the brain. However, they can induce seizures and transient neurologic deficits and may be applicable only for diseases restricted to the brain surface. Physiologically based strategies utilizing transport systems naturally present at the blood-brain barrier appear to be a more promising approach to brain delivery of antibodies. Cationization is a chemical treatment that causes the conversion of superficial carboxyl groups on a protein into extended primary amino groups. This is used to increase interactions of this protein with the negative charges at the luminal plasma membrane of the brain endothelial cells. The cationized protein can then undergo adsorptive mediated transcytosis through the blood-brain barrier. There are many problems yet to be solved in successfully carrying out in vivo applications of cationized antibodies. One of these problems is that cationization can cause damage to an antibody molecule and, thus, can compromise its binding affinity. Depending on the radiolabelling of the cationized antibodies, a serum inhibition phenomenon can possibly alter the pharmacokinetics and the organ distribution of these molecules. The antibodies can be cationized using various, synthetic (hexamethylenediamine) or naturally occuring (e.g., putrescine) polyamines. Hexamethylenediamine-induced and putrescine-induced brain uptakes of various antibodies and proteins have been shown, but the results obtained suggest that cationization with putrescine may be a more efficient approach to blood-brain barrier delivery. The development of animal or cellular models to check for therapeutic efficacy of cationized antibodies is necessary. In spite of the difficulties, the studies described in this paper indicate that cationization can be a realistic delivery strategy for carrying antibodies across the blood-brain barrier. The advances made in antibody technologies help generate more appropriate immunological structures for brain transfer with better effector functions and decreased immunogenicity or toxicity. Taken together, these two aspects can lead to further developments in treatment of intoxications caused by the clostridial neurotoxins.
Hervé
F
F
INSERM U26, Hôpital Fernand Widal, 200 rue du Faubourg Saint-Denis, 75475 Paris. francoise.herve@inserm.lrb.ap-hop-paris.fr
Ouzilou-Girod
J
J
Scherrmann
J M
JM
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D001812:Blood-Brain Barrier; D001905:Botulinum Toxins / Q000494:pharmacology / Q000506:poisoning; D001921:Brain / Q000378:metabolism*; D001927:Brain Diseases / Q000382:microbiology*; D002412:Cations; D003015:Clostridium Infections / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D013744:Tetanus Toxin / Q000494:pharmacology / Q000506:poisoning
D000906:Antibodies; D002412:Cations; D013744:Tetanus Toxin; D001905:Botulinum Toxins