One Mouse Per Patient

I

In 1981, at Stanford, a man with B-cell lymphoma on whom chemotherapy no longer had any effect received by vein an antibody made against his tumour and against no other in the world.

His name was Phillip Karr. He was treated by Richard Miller, in Ronald Levy's laboratory.

To make it you had to start from him. A B-cell lymphoma is the descent of a single cell that started copying itself without stopping, so that all the cells of the tumour are daughters of that one and all make the same antibody, with the same tip. That tip has a technical name, “idiotype”, and it is different in each person and in each tumour. It was the only mark on the planet that Karr's diseased cells carried and that no healthy cell of anybody's carried.

They took tumour out of him [a node biopsy]. They purified the antibody it made, injected it into mice and waited for the mouse to mount defences against that particular tip. Then they fused spleen cells of the mouse with myeloma cells, so that the factory would not die after a few days, and went on screening until they hit the line that recognised Karr's tip and no other.

Months of work for one patient.

Miller began with a very low dose and went up slowly. His nodes shrank; his platelets and blood count improved; the tumour disappeared.

Karr was in remission for more than thirty years. The case was published on 4 March 1982 in a Boston medical journal [volume 306, pages 517 to 522].

II

That was not a product and that is why nobody knew where to put it.

There was no batch, no indication and no price, because there was nothing to sell. What had been made worked against one tumour, and that tumour was inside one particular gentleman [one, with a postal address]. The next patient needed another mouse, another fusion, another screening and another few months. David Maloney, who was in that laboratory, summed it up years later in workshop terms. One antibody worked for one patient; a new one was needed for each new patient.

A few more suits were made. No industry can work like that.

So Levy and Miller abandoned the tip and went to the badge. On the surface of all B cells, diseased and healthy, there juts out a protein called CD20; it distinguishes nobody, everybody wears it, and for that very reason a thing that grabs hold of it can be mass-produced.

Out came a mouse antibody with the bottom half swapped for the human one, with a code name and a number. The first body to receive it entered a phase one trial in March 1993. There were fifteen patients and single doses of ten, fifty, a hundred, two hundred and fifty and five hundred milligrams per square metre of body surface [three people per step].

That body has no public name. It is a row in a dose escalation table.

The drug was approved on 26 November 1997 and was the first monoclonal antibody authorised against a cancer.

III

I have paid sixty-two euros to have mine counted.

It is a lymphocyte population test that can be ordered without a prescription at any private laboratory. Two tubes, a swab of cotton wool, a waiting room with a television with no sound —the automatic subtitles ran a second behind the mouths— and a car park that cost one twenty.

The report came by post four days later, with a table of values and a column of reference ranges beside it. The line that interested me says B lymphocytes, ninety-two cells per microlitre of blood, within normal.

Those cells wear the badge. They are mine, they are healthy and they are what the drug erases, because the drug cannot read the difference between a diseased B cell and a B cell of mine.

What I bought for sixty-two euros was nothing like a treatment. It was a reading of the target.

IV

An antibody is an enormous thing.

It weighs some hundred and fifty thousand daltons and is shaped like a Y; compared with an aspirin [a hundred and eighty daltons] it is a lorry next to a marble. It does not enter cells, does not cross into the brain and cannot be taken as a tablet, because the stomach would digest it the way it digests a steak. It travels through the blood and the lymph, which is where B cells are.

The two tips of the Y grab the badge. What decides the cell's fate is the other part, the foot of the Y, which is left jutting outwards like a handle.

From there three things happen, and all three are done by the body and not by the drug. A chain of proteins circulating in the blood recognises the handle, assembles on top of the cell and punctures its membrane. A macrophage passing by grabs the handle with the hand it has for that and swallows the whole cell. And the cell itself, with hundreds of badges grabbed at once, receives inside the order to switch itself off.

The foot of the Y is the reason the antibody has the human half. The mouse's handle does not fit the hands of a human macrophage, so they left the mouse the tips that know how to grab and put one of our handles underneath. That is the whole invention.

The body responds to this in the only way it can, which is by redoing the inventory. B cells vanish from the blood within days and take six to twelve months to come back.

There is an exception and it is the good part. The cells that have spent years making your lifelong antibodies —the tetanus ones from childhood, the measles ones— took the badge off on maturing and do not wear it. They survive. You keep the old defences and lose for a year the capacity to make new ones.

V

Between 1981 and 1997 the science did not change. What changed was who the thing was aimed at.

Karr's antibody knew who Karr was. It was made against a mark that existed only inside him, and that is why it did not touch one healthy cell. The absolute precision and the impossibility of selling it were the same fact.

The one that came afterwards needs to know nothing about you. It grabs a generic badge, and for the badge to be generic everything healthy has to wear it too; so that erasing the whole compartment stops being a side effect of the treatment and becomes its condition of manufacture.

The “magic bullet” the German dye industry sought for thirty years ended up being this. A mass drug demands a mass target, and a mass target is one you wear too.

VI

Against me: the bespoke suit was worse.

It took months, and somebody dying of a refractory lymphoma does not have months [they have weeks, with luck]. It was made for a handful of people in a single hospital in California [forty-odd in fifteen years]. Of those who received it afterwards, very few responded as he did, and nobody has fully explained why it went that way for Karr.

The generic one has treated millions of people, is on the World Health Organization's list of essential medicines and today is also given for arthritis, multiple sclerosis and kidney diseases. In those the aim is precisely to erase healthy B cells. Nostalgia for the tailor is a comfortable posture only somebody who is not on the waiting list can afford.

VII

I come back to the mouse.

There was a live mouse into which a man's tumour was injected so that it would make against it what the man could not make, and that mouse was of no use for the next patient. For the next one another animal and another tumour were needed. The medicine that came out of there consisted of ceasing to look at what each tumour has that is unrepeatable and keeping what they all have in common, which is also what we healthy ones have in common.

A hundred and forty-four years after the first vaccine, and forty-four before the liquid made in Philadelphia for a six-month-old baby, there was a medicine whose entire population was one gentleman in California.

Number of patients the antibody worked for: one.

Price: none, because it was never put on sale.

Manufacturing time: months, starting with a mouse.

A five-hundred-milligram vial of the one made in series today: three thousand five hundred and eighty-four dollars list price in its biosimilar version, and an ordinary course takes several.

Time the B cells it erases take to come back: six to twelve months.

What it cost me to count mine: sixty-two euros, with the car park on top.