Human monoclonal antibodies to group B streptococcus. Reactivity and in vivo protection against multiple serotypes.

Abstract

Group B streptococcal (GBS) infections cause significant mortality and morbidity among infants. Passive antibody immunotherapy has been proposed as treatment for infected infants. To this end, two human mAb-secreting cell lines were produced by EBV immortalization of human B cells. The mAbs were specific for the group B polysaccharide and bound to strains of all five serotypes as demonstrated by ELISA and crossed immunoelectrophoresis. The mAbs reacted and opsonized 100% (132/132) of the clinical isolates tested which represented all four capsule types. Both prophylactic and therapeutic protection with these mAbs were demonstrated in neonatal rats given lethal infections of types Ia and III human clinical isolates. These data indicate that a single human mAb directed against the group B carbohydrate can protect against GBS infections caused by the different serotypes. This antibody may be useful in the passive immunotherapy of infants infected with GBS.

Somatic Diversity in CDR3 Loops Allows Single V-Genes To Encode Innate Immunological Memories for Multiple Pathogens

“…Dglucose showed no ability to inhibit the binding of S.sJ1Ala or S.sJ5Gly to 23F, but it was able to inhibit binding by S.sJ1 at ∼10-fold greater concentration than that of L-rhamnose. The importance of the L chain encoded by IGKV3-11 in the recognition of Lrhamnose is also supported by observations of hypermutated anti-23F Abs that pair an L chain that uses IGKV3-11 with an H chain that uses another IGHV gene and not IGHV3-30 (6), as well as the fact that the IGKV3-11 gene was used in the L chain of an Ab that bound to Group B streptococcal polysaccharide, a distinct polysaccharide Ag that also exhibits an antennary L-rhamnopyranosyl group (25). Our evidence suggests that germline-encoded IGKV3-11 may encode residues in CDRL3 that contact L-rhamnose.…”

Pharmacokinetic and Pharmacodynamic Analysis of a Human Immunoglobulin M Monoclonal Antibody in Neonatal Macaca fascicularis

“…An average anticipated dosage of 20 mg/kg in human neonates is based on body weight extrapolations from studies in a neonatal rat infection model (8). This dosage was administered to monkey T8900 1 (1 7.8 mg/kg) and approximately 10 times this amount to monkey T89008 (230 mg/kg).…”

“…The functional activity or "pharmacodynamics" of the antibody in serum samples was quantitated following a protocol described previously (8). MAb-mediated opsonic activity in monkey T89008 serum samples was assayed against two GBS (capsule serotype 111) clinical isolates (COH 1 and type IIIR, provided by Drs.…”

“…To supplement current antibiotic therapy, we have developed human MAb with immunotherapeutic potential. Human IgM MAb produced against the group carbohydrate of GBS or the E. coli K1 capsule were found to protect against lethal infections in animal models (7,8). Although administration of human MAb does not have obvious risks, it is still necessary to insure the safety of individual MAb and the methods used for their preparation.…”

Production of a Human Monoclonal Antibody to a Synthetic Peptide by Active In Vivo Immunization Using a SCID Mouse Grafted with Human Lymphocytes.

“…So far, we have obtained only limited number of human monoclonal antibodies. These antibodies were established using human B cells which had already been sensitized in vivo with a pathological condition, such as an infectious or autoimmune disease (Grunow et al 1988;Martin et al 1988;Raff et al 1988;Nakamura et al 1988;Randen et al 1989).…”