It is some time since I first reported on the Spring meeting of the UKCLL Forum on monoclonal antibodies in CLL. Here at last is the second half of the meeting.
Geoff Hale invented Campath. He reported on the difficulties in estimating what happens to monoclonal antibodies once they have been injected. In comparison with small molecules, like standard chemotherapy drugs, antibodies often have non-linear pharmaco-dynamics; they have a much more restricted distribution space, often being confined to the vasculature and extra-vascular fluid with poor tissue penetration. They are broken down, not be metabolic activity, but by proteolysis; they are not cleared by the kidneys, but they are often immunogenic and cleared by an antibody response. They have a high affinity binding to their target, so that binding usually leads to clearance. The half-clearance time of IgG1, IgG2 and IgG4 is 3 weeks, while for IgM, IgA and IgG3 it is one week. However, high levels of antibodies are cleared more quickly. Clearance rates can be prolonged by altering glycosolation, by linking polyethylene glycol to the molecule or by making changes to the FcRB binding site.
The FcRB or Brambell receptor (which is present on the cells that line blood vessels and other tissues) is the means by which the long half life of antibodies is achieved (in this function it is known as FcRp – for protection). It also is responsible for the transference of antibodies across the placenta to the growing baby (here it is known as FcRN – for neonate. In some animals (but not in humans) it is also responsible for the transfer of antibodies from mother to child in the colostrum, the first few secretions of the breast after birth (FcRT for transport). The Brambell receptor is thus very important.
FW Rogers Brambell was Professor of Zoology at Bangor University in North Wales until 1968. As it happens he was the mentor of one of my colleagues at Southampton, Arthur Wild, and the PhD examiner of one-time Professor of Immunology at Southampton, Leslie Brent. (Leslie was famous as part of the team that discovered the mechanism of skin graft rejection – Medewar, Billingham and Brent). To complete the circle, Leslie Brent was the PhD supervisor of Lee Rayfield while he was in Southampton, and Lee is now Bishop of Swindon, and a colleague of mine on GTAC.
Arthur was able to give me some information about Rogers Brambell. He was born in Ireland in 1901. At the time of his birth, Ireland was part of the United Kingdom, but Brambell was born in the south, in fact in Dublin. His accent betrayed his southern origin; he couldn’t say his ‘th’. He’d say tree tousand trushes in te trees. At Aravon School he was thought rather dim; there was some question that he might be mentally retarded. He was good at nature study and things biological, however, and although there was some worry that he might never be able to make a living, he was advised to try farming ‘in the colonies’.
Despite his apparent unteachableness he went to university at Trinity College where he also did a PhD. Research in University College, London led to a DSc and he became in 1930 the Lloyd Roberts Professor of Zoology at one of the smallest universities in Britain, Bangor in North Wales where he established a well-regarded department of marine biology at Menai Bridge.
During the war, because of the Atlantic blockade by U-boats the Government was worried about feeding the people. Rabbits became an important study, but were becoming scarce. Of all the most unbelievable assignments, Brambell was given the task of increasing the fecundity of rabbits.
He began to examine the cause of rabbit miscarriages. He found the presence of fibrinogen in the blastocyst. How did it get there? It must have come from the rabbit mother’s blood. What other proteins managed to get there? Surprisingly immunoglobulins were found. So began the research which culminated in the discovery of the Brambell receptor with its threefold function.
Arthur remembers Brambell as an aloof, academic, aristocratic sort of man. He ran an efficient department that was focussed on research and was good to work for, but he was a bit detached from this present world. He used to go home at 4 o’clock in order to go fishing in lake on the Isle of Anglesey. His wife used to run him. A story is told of his wandering around Bangor with no money in his pockets. He went into his bank to withdraw some. They sent for the manager who explained, “Professor Brambell, you do not have an account here. The money is all in your wife’s name.” An innocent abroad.
For his research on the FcRn receptor Rogers Brambell was awarded the Gold Medal of the Royal Society. During his later academic life he was Dean of Faculty, twice vice-principal of the University, a member of the Agricultural Research Council, on the council of the Royal Society, a member of the University Grants Committee and the Chairman of a Royal Commission on factory farming. His commission’s report established that farm animals feel pain, and led to the banning of the debeaking of battery chickens. He bacme CBE in 1966.
He was a high-church Anglican and therefore almost certainly one of those English-Irish – not one of the hard-nosed Scots Presbyterians from the North; certainly not a Fenian and not one of the absentee-landlord English that exacerbated the potato famine. One of the English that stayed, lived and melded with the people, and adopted their soft southern ways.
Dead for 36 years, who remembers him now? After a long and academically successful career, could he not face the life outside University? When an influential man is himself debeaked, does it hurt? Is it beyond bearing? He died young. There is an entry in the Concise Dictionary of National Biography, but nothing in the Hutchinson Dictionary of Scientific Biography and nothing in the Oxford Companion to Medicine. On Google only his publications. And his receptor.