Preclinical studies with immunoconjugates.
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Animals↗
Biomedical subjects
Z Cunningham
Publications and source records attributed to Z Cunningham.
Specific in vitro anti-tumour activity of methotrexate-monoclonal antibody conjugates prepared using human serum albumin as an intermediary.
Methotrexate (MTX) is a folic acid antagonist widely used in the treatment of cancer but, like other such agents, has non-specific toxic side effects. With the aim of reducing these toxic effects, MTX was coupled to monoclonal antibodies (MoAb) in one of two ways; either (a) directly using an active ester derivative or (b) via human serum albumin (HSA), to act as an intermediary and so increase the amount of MTX bound. The MTX coupled directly to anti-Ly-2.1 antibody had approximately 10 molecules of MTX per antibody molecule, whereas the HSA coupled material had 24 molecules of MTX per antibody molecule. After coupling MTX directly to antibody there was a loss of potency of the MTX, and MTX-MoAb conjugates were 30-fold less potent than free MTX, although the antibody-coupled material was more specific than free MTX and bound only to the antibody-reactive target cells. By contrast, the MTX-HSA-MoAb conjugates were 3.5 times less potent than free MTX and were 8.5 times more potent than MTX-MoAb conjugates. Thus, by increasing the amount of drug bound to antibody, more toxic conjugates were made--an important principle for the use of such conjugates for the treatment of cancer in man.
Animals↗
Anti-tumour activity of aminopterin-monoclonal antibody conjugates; in vitro and in vivo comparison with methotrexate-monoclonal antibody conjugates.
Two related folate antagonists aminopterin (AMN) and methotrexate (MTX) were used to produce drug-antibody conjugates and their tumouricidal effects compared in vitro and in vivo. Active ester derivatives were produced with the use of N-hydroxysuccinimide (NHS) and covalently coupled to monoclonal antibodies (MoAb) reactive with murine cell surface antigens; approximately 11 molecules of AMN or 13 molecules of MTX were specifically bound per molecule of anti-Ly-2.1, with good retention of antibody activity and protein recovery. AMN was a more effective inhibitor of tumour cell growth in vitro than MTX, and AMN-anti-Ly-2.1 conjugates were also more potent in vitro than MTX-anti-Ly-2.1 conjugates. Although there was some loss of drug activity on binding to antibody, AMN-MoAb conjugates were as toxic as free MTX. However, in contrast to free drugs (which can act on any target), the toxicity of drug-MoAb conjugates was entirely specific for the target cells. In addition, AMN-MoAb conjugates were effective anti-tumour agents in vivo, and in mice bearing established thymoma grafts AMN-MoAb conjugates inhibited tumour proliferation better than MTX-MoAb, free AMN or MTX or antibody alone. AMN coupled to specific MoAb is a potentially useful agent for immunotherapy and is of particular relevance in man as free AMN has been discarded because of its systemic toxicity. Now, coupled with antibody, there will be specific tumouricidal effects in the absence of toxicity.
Aminopterin↗