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Issue #75: The monoclonal antibody story part 6: the marvellous mAbs

20 Sep 2021

Issue #75: The monoclonal antibody story part 6: the marvellous mAbs

If you, or your older relatives, are being treated for some chronic condition by the regular subcutaneous (SC) or intravenous (IV) inoculation of a ‘drug’ – or ‘biological’ – with ‘mab’ at the end of the proprietary name, the ‘therapeutic’ in question is a monoclonal antibody. Being able to make human mAbs at will – using approaches like phage display (#75) to find the key immunoglobulin genes (Ig) – has revolutionised many areas of medicine. The first medically important ‘phage display’ mAb was Adalumimab, which is also called Humira, so not all these ‘therapeutics’ have that mab ending. Well known in that category is Herceptin (also called Trastuzumab), which targets the human epidermal growth factor receptor 2 (Her2) molecule that can be over-expressed on the surface of breast, and some other, cancer cells.

Targeting an overexpressed ‘self’ protein like Her2, which is at abnormally high levels on the surface of about 20 per cent of breast cancers, is one type of cancer treatment, but there’s an even more revolutionary mAb therapy that works via re-activating our own immune response. That discovery led to a further mAb Nobel Prize, in 2018 for Medicine, to Jim Allison from the MD Anderson Cancer Hospital in Houston, and Tasuku Honjo from Kyoto University. We’d known for years that cancers in both mice and humans often contain large numbers of immune T cells, including the CD8+ ‘killers’ (#33, #34), that are specific for the tumour in question but just don’t seem to be doing anything much. Over the years, researchers isolated these ‘dozey’ T cells from ‘debulked’ (surgical excision of cancer lumps) tumours, stimulated them in different ways in culture systems, then tried injecting these (hopefully) ‘energized’ immune lymphocytes (#39, #40) back into the suffering patient. Disappointingly, though there were some successes, there weren’t enough. What was happening here? These cancer-resident T cells were alive, but they seemed to have gone into some inert ‘Snow White’ sleeping mode. And the ‘seven dwarves’ (the involved scientific community) just weren’t able to wake them up as they awaited the ‘Princely kiss’.

What Allison, Honjo and others showed us was that these ‘tumour-resident’ T cells were, in fact, switched-off, with the ‘off-switch’ on the T cell surface working via ‘immune check-point’ proteins (called CTLA-4 and PD-1). The role of these molecules in normal biology is to stop us from being overwhelmed by continuously multiplying lymphocytes, a necessity for maintaining the ‘homeostasis’ that keeps white blood cells at tolerable levels. Further experiments, at first in culture systems and then in mice, indicated that injecting mAbs specific for CTLA-4 or PD-1 might indeed provide that ‘Princely kiss’ by reactivating the tumour-resident T cells so that they would kill the tumour and ‘save’ the mouse.

This was brilliant! We didn’t even need to know what the actual TCRs (T cell receptors) on these potential killers were recognising (#18, #33), a subject that had involved enormous effort by many researchers. Just the fact that they were ‘hanging out’ in the tumor told us that they were, in effect, specific for the cancer in question. But while the awakening ‘kiss’ of the check point specific mAbs worked in laboratory mice, would that also be true for people with cancer?

Realising the enormous potential, Allison, a basic scientist, left UC Berkeley – which does not have a medical school – and moved first to the Memorial  Sloan Kettering Cancer Center in New York, then to MD Anderson back in his home state of Texas, so that he could work with clinical oncologists and trial humanised mAbs to CTLA-4 as a cancer therapy. Other therapeutic research focused on blocking PD-1 (or its receptor PD-L-1), in efforts led by Arelene Sharpe and Gordon Freeman at Harvard and Leiping Chen at Yale, went down the same path. In all cases, the ‘Princely kiss’ of mAb therapy led, for example, to the miraculous recovery of a percentage of melanoma patients who would otherwise have died. Subsequently, this therapeutic approach has been extended successfully to a spectrum of other cancers

Targeting other somewhat ubiquitous immune system molecules, a spectrum of mAbs specific for various cytokines is also proving to be of immense clinical value. The first of these to be blocked by mAb therapy with substantial clinical benefit was TNFa (tumor necrosis factor a). Very early on, researchers made mAbs to TNFa in the hope of providing a rapid treatment for one of the worst problems in medicine, acute septic shock, where masses of TNFa are made and people go rapidly into irreversible decline. Sadly, it didn’t work but, in London, two medical doctors at the Kennedy Institute of Rheumatology, Australian-educated Mark Feldmann and Indian Ravinder (Tiny) Maini, infused the anti-TNFa-mAb into rheumatoid arthritis patients. Here, the mAb tratment proved to be enormously beneficial in a percentage of people suffering from this horrible and painful inflammatory disease. They were jointly recognised by Sweden’s other, major science prize, the Crafoord in 2000 and, in 2001, the US Albert Lasker Medical Science Award

Setting it Straight by Laureate Professor Peter Doherty Archive