Suppression of well-established tumour xenografts by a hybrid-hybrid monoclonal antibody and vinblastine.

The hybrid-hybrid monoclonal antibody 28-19-8 has specificity for the tumour-associated antigen carcinoembryonic antigen and the vinca alkaloids. This bifunctional antibody has been used to target unmodified vinblastine sulphate to well-established MAWI human tumour xenografts implanted in nude mice. The highly significant suppression of tumour growth achieved throughout treatment has also been sustained for over 2 months after the withdrawal of treatment. Histological examination of excised tumours from treated animals has shown profound changes in their morphology when compared with tumours from control animals. Cells in tumours that had started to grow again after withdrawal of therapy were shown still to express carcinoembryonic antigen, the target antigen recognised by the bispecific antibody.

Training general practitioners to improve their recognition of emotional disturbance in the consultation.

The detection of emotional disturbance by general practitioners in the consultation is known to be low. This study measured the detection rates of emotional disturbance among 10 established principals in general practice, as compared with the general health questionnaire, before and after 10 months of training. The training comprised a fortnightly seminar based around video recordings of ordinary consultations. The results showed that nine of the 10 doctors improved their ability to identify cases while one over-diagnosed cases following the training. The general health questionnaire detected emotional disturbance in 51.5% of the patients studied. During the seminars it became apparent that factors both within the doctor and the patient prevented detection of emotional disturbance and these are described. It is concluded that diagnostic accuracy depends on the interaction between doctor and patient, and that this has implications for the organization of general practice both in terms of longer consultation times and of adequate support for the doctor.

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

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 tumour. The hybrid-hybrid MAb localises specifically onto CEA-expressing tumour tissue and, furthermore, is able to target Vinca alkaloids to tumour. 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.

Specific in vitro and in vivo drug localisation to tumour cells using a hybrid-hybrid monoclonal antibody recognising both carcinoembryonic antigen (CEA) and vinca alkaloids.

By using a bispecific monoclonal antibody recognising both carcinoembryonic antigen (CEA) and the cytostatic vinca alkaloid drugs we have been able to show specific tumour localisation of vinca alkaloids. In vitro studies with sections of human colorectal tumours have demonstrated that the hybrid-hybrid 28.19.8 monoclonal is able to specifically localise vindesine to cells expressing CEA. Furthermore, the hybrid-hybrid 28.19.8 localises in vivo preferentially to tumour tissues in nude mice bearing the MAWI human xenograft tumour. This tumour-bound hybrid-hybrid monoclonal antibody induces profound changes in the bio-distribution of vinca alkaloid drugs, targeting them specifically to tumour tissues.

Increased therapeutic effect of vinca alkaloids targeted to tumour by a hybrid-hybrid monoclonal antibody.

Unmodified vinblastine (VLB) targeted through one of the antigen combining sites of the hybrid-hybrid 28.19.8 monoclonal is potentially more effective in suppressing the growth of established MAWI tumour xenografts implanted on nude mice than free VLB in the absence of the targeting agent, presumably due to an increased local drug concentration. Our efficacy results in this study suggest that drug, specifically removed from the circulation by hybrid-hybrid antibody previously located to the tumour mass, can be made available in a pharmacologically active from. Histological analysis of the treated tumours revealed dramatic changes in the tumour organisation with only a few surviving tumour cells with altered morphology.

Drug localisation and growth inhibition studies of vindesine-monoclonal anti-CEA conjugates in a human tumour xenograft.

The distribution of tritiated vindesine (3H-VDS) was studied in the tissues and tumours of athymic mice bearing a human colorectal tumour xenograft. Selective tumour localisation was obtained when 3H-VDS was injected as a conjugate with a monoclonal anti-CEA antibody (11.285.14) but not as a conjugate with a non-binding monoclonal IgGl (Ag8) or as free succinoyl-VDS. The amounts of VDS that localised in the tumour following injections of 3H-VDS-11.285.14 increased in proportion to the amount injected, over a wide dose range. Conjugates prepared using the Fab fragments of 11.285.14 showed no evidence of selective tumour uptake in comparison with normal tissues. Various dose levels of VDS-11.285.14 conjugate and free VDS were studied for effects on the growth of the tumour xenograft. A growth inhibition of 50% was obtained at 1.5 mg/kg with free VDS and at 2.5 mg/kg with conjugated VDS. The conjugate was, however, considerably less toxic.

Antitumor properties of vindesine-monoclonal antibody conjugates.

The anticancer alkaloid vindesine (VDS) was conjugated to four mouse monoclonal antibodies recognizing human tumor-associated antigens. The antibodies were 96.5 (antimelanoma, IgG2a); 791T/36 (antiosteogenic sarcoma, IgG2b); 11.285.14, and 14.95.55 (anticarcinoembryonic antigen, IgG1 and IgG2a respectively). Conjugates VDS-96.5 and VDS-791T/36 were tested in vitro and shown to be specifically cytotoxic for target cells expressing the appropriate antigen. The in vivo effects of the antibodies and conjugates were tested against human tumor xenografts in athymic or immunodeprived mice using multiple treatments. Conjugate VDS-96.5 retarded the initial growth of a melanoma xenograft, whereas free antibody was without effect. Similarly, VDS-791T/36 but not free antibody retarded the growth of osteogenic sarcoma 791T. The most marked antitumor effects observed were those obtained with VDS conjugates of the anti-CEA antibodies against a colorectal tumor xenograft. Antibody 14.95.55 suppressed tumor growth both alone and as a VDS conjugate, whereas 11.285.14 produced only a slight effect alone but an almost complete and lasting suppression of tumor growth as a VDS conjugate. Free VDS had little effect at nontoxic levels. Acute studies showed that VDS-11.285.14 conjugate was considerably less toxic than free VDS in Balb/c mice.