Cooperative mixtures of bispecific F(ab')2 antibodies for delivering saporin to lymphoma in vitro and in vivo

Journal Article · Wed May 01 00:00:00 EDT 1991 · Cancer Research; (United States)

OSTI ID:5670108

French, R R; Courtenay, A E; Ingamells, S; Stevenson, G T; Glennie, M J ^[1]

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1. General Hospital, Southampton (England)

We report that selected combinations of two or more monoclonal bispecific F(ab')2 antibodies (BsAbs) far outperform single derivatives in the delivery of the ribosome-inactivating protein, saporin, to guinea pig L2C leukemic cells. Throughout the work, BsAbs were constructed by thioether-linking the hinges of two Fab'gamma, one from monoclonal anti-L2C-idiotype antibody and the other from anti-saporin antibody. The latter was either affinity-purified rabbit polyclonal or one of a panel of five mouse monoclonal antibodies. In vitro cytotoxicity studies showed that, though all derivatives were effective, the BsAb made with the polyclonal antibody was always 10 to 20 times more potent than those made with a monoclonal antibody in yielding 50% inhibition of (3H)leucine uptake. This superior activity could be matched by selective mixtures of two or more of the monoclonal derivatives. Furthermore, in immunotherapeutic delivery of saporin to tumor, a pair of BsAbs performed significantly better than did either individually. Binding and uptake studies with radiolabeled saporin demonstrated a 20-fold increase in functional affinity when saporin was held at the cell surface by an appropriate BsAb mixture rather than by a single BsAb. In contrast, only small differences were recorded in the rate at which saporin was internalized as a result of the same maneuver. We conclude that the improved performance of combinations of BsAbs arises from their ability to provide multiple linkages between saporin molecules and cell surfaces, increasing the functional affinity with which saporin is tethered to the cell, but, in this system at least, having only a minor effect on the rate at which it is internalized. Cocktails of two or more BsAbs, selected to bind to multiple epitopes on ribosome-inactivating proteins could provide an important new strategy in immunotherapy.

• OSTI ID: 5670108
• Journal Information: Cancer Research; (United States), Vol. 51:9; ISSN 0008-5472
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
LEUKEMIA
RADIOIMMUNOTHERAPY
MONOCLONAL ANTIBODIES
SPECIFICITY
GUINEA PIGS
LEUCINE
MICE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
TUMOR CELLS
AMINO ACIDS
ANIMAL CELLS
ANIMALS
ANTIBODIES
CARBOXYLIC ACIDS
DISEASES
HYDROGEN COMPOUNDS
IMMUNE SYSTEM DISEASES
IMMUNOLOGY
IMMUNOTHERAPY
ISOTOPE APPLICATIONS
MAMMALS
MEDICINE
NEOPLASMS
NUCLEAR MEDICINE
ORGANIC ACIDS
ORGANIC COMPOUNDS
RADIOIMMUNOLOGY
RADIOLOGY
RADIOTHERAPY
RODENTS
THERAPY
VERTEBRATES
550604* - Medicine- Unsealed Radionuclides in Therapy- (1980-)