Tumour therapy with vinca alkaloids targeted by a hybrid-hybrid monoclonal antibody recognising both CEA and vinca alkaloids

Abstract

The functional properties of a hybrid-hybrid monoclonal antibody (MAb) recognising both CEA and Vinca alkaloids have been explored in vivo in nude mice xenografted with MAWI, a human colorectal turnour. The hybrid-hybrid MAb localises specifically onto CEA-expressing tumour tissue and, furthermore, is able to target Vinca alkaloids to turnour. Under the influence of the hybrid-hybrid MAb a profound change in the bio-distribution patterns of the Vinca alkaloids is observed. Therapeutic data produced in this in vivo model indicates that treatment with Vinca alkaloids in conjunction with hybrid-hybrid MAb is significantly more effective in suppressing tumour growth of established tumour xenografts than the Vincas when given as free drug.The covalent coupling of drugs or toxins to tumour-specific MAbs and their potential use as therapeutic agents has been actively explored in the recent past as a way to overcome the inherent lack of specificity associated with conventional chemotherapy. Conjugates of vindesine with MAbs recognising osteosarcoma, melanoma or carcinoembryonic antigens have shown therapeutic potential with reduced drug toxicity (Rowland et al., 1985), although these (19874 using a hybrid-hybrid MAb with specificity to both the tumour-associated antigen and the cytotoxic drug. In this model the drug is delivered to the tumour through the antigen-combining site of the bispecific antibody. We report here that drug delivered in such a way is far more efficacious than an equivalent amount of free drug. MATERIAL AND METHODS Mice and xenograftsOutbred nu/nu athymic mice were bred and maintained in isolators (Isotec, Bicester, UK). Xenograft growth was initiated by S.C. inoculation of 0.2 ml of a suspension of MAWI, a human colorectal carcinoma (Rowland et al., 1986). Hybrid-hybrid monoclonal antibodyThe construction, affinity purification and the in vitro and in vivo properties of the hybrid-hybrid 28.19.8 MAb have been described (Corvalan et al., 1987a, b and c). For in vivo studies affinity purified 28.19.8 MAb was stored at 1 mg/ml in phosphate buffered saline (PBS), filtered sterile (0.2 pm) and maintained at 4°C until used. Further dilutions were made in PBS shortly before use. 3H-Vinblastine in in vivo localisation studiesGroups of 3 mice with 3-4 weeks established MAWI xenografts were injected i.p. with 1 mg of affinity purified hybrid-hybrid 28.19.8 MAb or PBS for the control group either at 7 or 3 days before, or on the same day as a mixture of vinblastine sulphate (VLB) and 3H-VLB (Amersham International, Little Chalfont, UK) as tracer. At days 1 and 7 after the injection, mice were killed and dissected. Weighed samples of tumour, visceral organs and plasma were then transferred to scintillation vials, processed (Rowland et al., 1986), and counted using a beta counter (1217 Rackbeta, LKB-Wallac, Bromma, Sweden). The results were expressed as nanograms of VLB localised per gram of tissue. In vivo turnour inhibition studiesThe in vivo effects of Vinca alkaloids targeted to tumour by hybrid-hybrid 28.19...

Does Bougainvillea spectabilis protect Swiss Albino Mice from Aflatoxin-induced Hepatotoxicity?

“…Hence, it can be accomplished that the hepatoprotective effects of EEBs could be attributed to its various phyto-constituents and might be responsible for suppressing the toxicity initiated by Aflatoxin B 1 . Alkaloids were also known for its anti-tumour property (Corvalan et al, 1988;Jiang et al, 2016). From the experimental findings, it can be inferred that concurrent administration of AFB 1 along with EEBs has significantly reversed the altered levels of LPO and antioxidant enzymes.…”

Recombinant approaches to IgG-like bispecific antibodies

“…In this setting, one arm of the BsAb binds an antigen expressed on the cell targeted for destruction, and the other arm binds a chemotherapeutic drug, radioisotope, or toxin. The naked BsAb is administered first, and after sufficient time has passed for the BsAb to bind tumor cells and to clear from normal tissue, the cytotoxic molecule is delivered, with rapid accumulation in the tumor, because of its affinity for the tumor bound BsAb [21][22][23][24][25] . Recently, a novel concept has emerged -the development of BsAb that target two tumor-associated antigens (eg, growth factor receptors) for down-regulation of multiple distinct cell proliferation/survival pathways, which provides enhanced antitumor activity [26][27][28] .…”

Monoclonal antibodies for imaging and therapy

“…Hybrid antibodies with dual specificities can be produced by the cell fusion of two Ig producing cell lines (Milstein & Guello, 1983;Clark & Waldmann, 1989) or by chemically conjugating two monomeric Fab fragments (Perez et al, 1985). Hybrid antibody may be capable of targeting diagnostic or therapeutic radioisotopes such as indium-ill and yttrium-90 (Goodwin, 1987) or targeting drug (Corvalan et al, 1988) or toxins (Webb et al, 1985) to cells expressing appropriate cell surface antigens. Of greater interest, perhaps, may be the ability of these bispecific antibodies to induce potent tumour cell killing by activated T-cells if the bispecific antibody can cross-link T-cells and antigens on the surface of tumour cells (Clark & Waldman, 1989;Canevari et al, 1988).…”