美国国家公共电台 NPR--How monoclonal antibodies lost the fight with new COVID variants

How monoclonal antibodies lost the fight with new COVID variants¹

Transcript²

Monoclonal antibodies were once the star of COVID-19 outpatient treatments. Since they first became available in 2020 – even before the first vaccines³ – more than 3.5 million infusions⁴ of the factory-grown proteins have been given to patients in the U.S. to help reduce risk of hospitalization.

But one by one, different monoclonal treatments have lost their efficacy against new variants of the coronavirus. The rise of Paxlovid antiviral pills earlier this year, further dented⁵ their appeal.

Now, a new wave of omicron subvariants that are the best yet at evading⁶ the immune system's current defenses have taken over in the U.S. They're expected to knock out bebtelovimab, the last monoclonal antibody treatment standing⁷ against the coronavirus. Soon, it'll join bamlanivimab, casirivimab, sotrovimab and others in the graveyard⁸ of monoclonals that once targeted past COVID strains until they were outflanked by variants that evaded⁹ their protection.

"Monoclonals had their day, like the Model T or the biplane," says Carl Dieffenbach, director of the Division of AIDS at the National Institutes of Health, and lead of the NIH's Antiviral Program for Pandemics, "Now it's time to move on."

Not everyone entirely¹⁰ agrees. Monoclonals are still useful, some doctors say, for treating a vulnerable population.

"There are severely¹¹ immunosuppressed patients that are not likely to mount an immune response to the virus, even if you treat them with antiviral drugs," says Dr. Raymund Razonable, an infectious disease specialist in the transplant division at the Mayo Clinic. "This is the group that is going to be the most affected¹² by the absence of antibody-based therapies."

What's more new research is underway to develop new types of monoclonal antibodies that could even hold up against new variants.

How monoclonals work — and what they're up against

Monoclonal antibody treatments have always had a major weakness – they're easily outmaneuvered by new COVID strains. It's a flaw that's baked into how they work.

Monoclonal antibodies are lab-grown proteins that supplement your body's immune system – which, in most people, is naturally producing antibodies to hunt for possible threats all the time.

"You and I and every human being that has a functioning immune system is walking around with probably trillions of totally different antibody molecules¹³ just circulating in our blood," says Derek Lowe, a chemist and blogger for the journal Science, "Every one of us has a totally different suite¹⁴ of them. There are more of them than there are stars in the sky."

The tiny, Y-shaped proteins lurk¹⁵ in the blood in low concentrations, "waiting and waiting until they happen to bump into something that they stick to really well, and they find their soulmate, basically," Lowe explains. That "soulmate" is an antigen – a foreign substance that's entered the bloodstream, like a bacterial¹⁶ protein or a virus or a pollen¹⁷ grain.

Once a monoclonal antibody finds its soulmate — in the case of COVID, a specific part at the tip of the SARS-CoV-2 virus – it binds¹⁹ to the surface of the antigen. Then, it sends out signals to the immune system, "like hey, I've got a live one," Lowe says.

The most powerful antibodies can stop the virus in its tracks just by binding²⁰ to it. For instance, "if you have an antibody that sticks to the tip of the spike²¹ protein at the business end of the virus – just the fact that it is stuck tightly to that means the virus cannot infect a cell," says Lowe.

The spike protein has been the target of all the monoclonal antibody treatments that go after the virus thus far. But it's been a fickle²² soulmate, changing with new variants, leaving the monoclonal antibodies adrift in the bloodstream with nowhere to bind¹⁸.

Companies have stopped bringing these monoclonals to market. The federal government stopped promising²³ to buy them in quantity, making it a riskier²⁴ bet for companies.

"There are antibodies out there, but nobody has the $200 million to develop it," Dieffenbach says, citing costs that include producing the antibodies, running trials and getting them authorized²⁵ by the Food and Drug Administration. Some companies figured it wasn't worth it, for a product that was likely to become obsolete²⁶ in a matter of months, he says.

To be clear, these are antibody treatments for outpatient treatment. There is a different kind of monoclonal antibody treatment for hospitalized patients that remains²⁷ viable²⁸. Actemra, as it's called, is not susceptible²⁹ to virus mutation³⁰ because it targets the body's immune reaction to the virus, rather than the virus itself.

New directions in research, and a potential comeback

There might still be hope for monoclonals. Drugmakers and researchers at government agencies are now retooling³² the strategy, looking for monoclonal antibodies that could last.

"Initially³³, the focus was, 'let's just find the most potent³¹ antibodies,'" says Joshua Tan, chief of the Antibody Biology Unit at NIH. "Now, there's awareness³⁴ that we need to find antibodies that are likely to work against not just the [current version of the] coronavirus, but whatever may come."

In his lab in Rockville, Md., Tan and the researchers who work with him are looking for antibodies that target parts of the virus that have stayed the same on several different viruses within the larger coronavirus family. "We're looking at other parts of the spike protein that may be more consistent and may be harder to mutate," Tan says.

To achieve this, researchers in Tan's lab are taking immune cells from the blood of patients that have recovered from COVID, and pelting³⁵ them with tiny plastic pellets covered with spike proteins from different, older coronaviruses to see which cells respond. "Not the [COVID] variants, but SARS-CoV-1, SARS-CoV-2, MERS [etc.]," post-doctoral researcher Cherrelle Dacon clarifies. "These are seven different coronaviruses, all of which infect humans."

The immune cells that react to several different coronaviruses are making antibodies that bind to a part of the spike protein that's staying the same across them.

It's a painstaking³⁶ process: Isolating³⁷ individual immune cells, finding the ones that make antibodies in response to various spike proteins — and then using those to make more antibodies that they can scale up, analyze³⁸ and test, to figure out what on the virus they're actually binding to. The process takes about three to four months each cycle, Tan says.

Tan says the good news is that they've found some antibodies that stick to multiple different coronaviruses. They published some of the results earlier this summer in Science.

Left: Tan holds a chip ready to be loaded with immune cells that will be be sorted and tested against different viruses. Right: The screen of the Beacon³⁹, a machine that isolates⁴⁰ individual immune cells so researchers can test which ones respond strongly to more than one coronavirus.

Pien Huang/NPR

But the problem the researchers have come up against is that the monoclonal antibodies they've found are not so potent. Tan says there seems to be a tradeoff – between how well a monoclonal antibody against COVID-19 works, and how long it lasts before the virus ditches the antibody's target.

An analogy: If the coronavirus had human body parts (which it doesn't) the old, highly effective monoclonals hit the virus's spike protein squarely on the nose. In contrast, the new monoclonals Tan is finding try to grab it by the armpit. "One of the issues appears to be that it's harder to reach those parts," Tan says, "What the broader, less potent [antibodies] need is for the spike protein to shift in shape" in order for them to grab it.

Tan is working to find ways around this tradeoff. He says you can potentially modify the antibody, change out parts of it to increase its potency⁴¹ – a process that's largely theoretical at the moment, and will take some time to work out.

So while Tan and other researchers work on the next generation of monoclonal antibodies – ones that work well against all kinds of coronaviruses, maybe even future pandemic ones – the nation is entering a long lull⁴² with no monoclonal antibody treatments that work against dominant⁴³ strains of SARS-CoV-2.

"The disappointment is there because you're losing a really good drug," says Razonable. "But you focus on the next options. The virus adapts, and we also adapt based on what we have available."

Luckily, as Tan and others pursue the long game with antibodies, there are other treatments, like Paxlovid pills and remdesivir infusions, that still work against COVID.

And the research on and rapid development of antibody treatments has opened up possibilities beyond COVID. "It has improved the production of monoclonals for cancer, for immunologic diseases," says Dieffenbach, "It's going to be easier to produce monoclonals in the future because of the lessons learned from SARS-CoV-2. Nothing was wasted here."

1 variants   

n.变体( variant的名词复数 )；变种；变型；（词等的）变体

参考例句：

• Those variants will be preserved in the'struggle for existence". 这些变异将在“生存竞争”中被保留下来。 来自辞典例句
• Like organisms, viruses have variants, generally called strains. 与其他生物一样，病毒也有变种，一般称之为株系。 来自辞典例句

2 transcript   

n.抄本，誊本，副本，肄业证书

参考例句：

• A transcript of the tapes was presented as evidence in court.一份录音带的文字本作为证据被呈交法庭。
• They wouldn't let me have a transcript of the interview.他们拒绝给我一份采访的文字整理稿。

3 vaccines   

疫苗，痘苗( vaccine的名词复数 )

参考例句：

• His team are at the forefront of scientific research into vaccines. 他的小组处于疫苗科研的最前沿。
• The vaccines were kept cool in refrigerators. 疫苗放在冰箱中冷藏。

4 infusions   

n.沏或泡成的浸液（如茶等）( infusion的名词复数 )；注入，注入物

参考例句：

• Intravenous infusions are also used to administer medications. 静脉输液也可作为一种给药方法。 来自辞典例句
• INTERPRETATION: GKI infusions significantly reduced plasma glucose concentrations and blood pressure. 结论：静脉滴注GKI显著降低血压和血糖浓度。 来自互联网

5 dented   

v.使产生凹痕( dent的过去式和过去分词 )；损害；伤害；挫伤（信心、名誉等）

参考例句：

• The back of the car was badly dented in the collision. 汽车尾部被撞后严重凹陷。
• I'm afraid I've dented the car. 恐怕我把车子撞瘪了一些。 来自《简明英汉词典》

6 evading   

逃避( evade的现在分词 )； 避开； 回避； 想不出

参考例句：

• Segmentation of a project is one means of evading NEPA. 把某一工程进行分割，是回避《国家环境政策法》的一种手段。 来自英汉非文学 - 环境法 - 环境法
• Too many companies, she says, are evading the issue. 她说太多公司都在回避这个问题。

7 standing   

n.持续，地位；adj.永久的，不动的，直立的，不流动的

参考例句：

• After the earthquake only a few houses were left standing.地震过后只有几幢房屋还立着。
• They're standing out against any change in the law.他们坚决反对对法律做任何修改。

8 graveyard   

n.坟场

参考例句：

• All the town was drifting toward the graveyard.全镇的人都象流水似地向那坟场涌过去。
• Living next to a graveyard would give me the creeps.居住在墓地旁边会使我毛骨悚然。

9 evaded   

逃避( evade的过去式和过去分词 )； 避开； 回避； 想不出

参考例句：

• For two weeks they evaded the press. 他们有两周一直避而不见记者。
• The lion evaded the hunter. 那狮子躲开了猎人。

10 entirely   

ad.全部地，完整地；完全地，彻底地

参考例句：

• The fire was entirely caused by their neglect of duty. 那场火灾完全是由于他们失职而引起的。
• His life was entirely given up to the educational work. 他的一生统统献给了教育工作。

11 severely   

adv.严格地；严厉地；非常恶劣地

参考例句：

• He was severely criticized and removed from his post.他受到了严厉的批评并且被撤了职。
• He is severely put down for his careless work.他因工作上的粗心大意而受到了严厉的批评。

12 affected   

adj.不自然的，假装的

参考例句：

• She showed an affected interest in our subject.她假装对我们的课题感到兴趣。
• His manners are affected.他的态度不自然。

13 molecules   

分子( molecule的名词复数 )

参考例句：

• The structure of molecules can be seen under an electron microscope. 分子的结构可在电子显微镜下观察到。
• Inside the reactor the large molecules are cracked into smaller molecules. 在反应堆里，大分子裂变为小分子。

14 suite   

n.一套(家具)；套房；随从人员

参考例句：

• She has a suite of rooms in the hotel.她在那家旅馆有一套房间。
• That is a nice suite of furniture.那套家具很不错。

15 lurk   

n.潜伏，潜行；v.潜藏，潜伏，埋伏

参考例句：

• Dangers lurk in the path of wilderness.在这条荒野的小路上隐伏着危险。
• He thought he saw someone lurking above the chamber during the address.他觉得自己看见有人在演讲时潜藏在会议厅顶上。

16 bacterial   

a.细菌的

参考例句：

• Bacterial reproduction is accelerated in weightless space. 在失重的空间，细菌繁殖加快了。
• Brain lesions can be caused by bacterial infections. 大脑损伤可能由细菌感染引起。

17 pollen   

n.[植]花粉

参考例句：

• Hummingbirds have discovered that nectar and pollen are very nutritious.蜂鸟发现花蜜和花粉是很有营养的。
• He developed an allergy to pollen.他对花粉过敏。

18 bind   

vt.捆，包扎；装订；约束；使凝固；vi.变硬

参考例句：

• I will let the waiter bind up the parcel for you.我让服务生帮你把包裹包起来。
• He wants a shirt that does not bind him.他要一件不使他觉得过紧的衬衫。

19 binds   

v.约束( bind的第三人称单数 )；装订；捆绑；（用长布条）缠绕

参考例句：

• Frost binds the soil. 霜使土壤凝结。 来自《简明英汉词典》
• Stones and cement binds strongly. 石头和水泥凝固得很牢。 来自《简明英汉词典》

20 binding   

有约束力的，有效的，应遵守的

参考例句：

• The contract was not signed and has no binding force. 合同没有签署因而没有约束力。
• Both sides have agreed that the arbitration will be binding. 双方都赞同仲裁具有约束力。

21 spike   

n.长钉，钉鞋；v.以大钉钉牢，使...失效

参考例句：

• The spike pierced the receipts and held them in order.那个钉子穿过那些收据并使之按顺序排列。
• They'll do anything to spike the guns of the opposition.他们会使出各种手段来挫败对手。

22 fickle   

adj.(爱情或友谊上)易变的，不坚定的

参考例句：

• Fluctuating prices usually base on a fickle public's demand.物价的波动往往是由于群众需求的不稳定而引起的。
• The weather is so fickle in summer.夏日的天气如此多变。

23 promising   

adj.有希望的，有前途的

参考例句：

• The results of the experiments are very promising.实验的结果充满了希望。
• We're trying to bring along one or two promising young swimmers.我们正设法培养出一两名有前途的年轻游泳选手。

24 riskier   

冒险的，危险的( risky的比较级 )

参考例句：

• Now they are starting to demand higher returns on riskier assets. 而今他们开始在风险更高的资产上要求更高的回报。
• The problem with that: RIM's business is getting riskier every quarter. 不过问题也随之而来：RIM面临的业务风险正逐季增大。

25 authorized   

a.委任的，许可的

参考例句：

• An administrative order is valid if authorized by a statute.如果一个行政命令得到一个法规的认可那么这个命令就是有效的。

26 obsolete   

adj.已废弃的，过时的

参考例句：

• These goods are obsolete and will not fetch much on the market.这些货品过时了，在市场上卖不了高价。
• They tried to hammer obsolete ideas into the young people's heads.他们竭力把陈旧思想灌输给青年。

27 remains   

n.剩余物，残留物；遗体，遗迹

参考例句：

• He ate the remains of food hungrily.他狼吞虎咽地吃剩余的食物。
• The remains of the meal were fed to the dog.残羹剩饭喂狗了。

28 viable   

adj.可行的，切实可行的，能活下去的

参考例句：

• The scheme is economically viable.这个计划从经济效益来看是可行的。
• The economy of the country is not viable.这个国家经济是难以维持的。

29 susceptible   

adj.过敏的，敏感的；易动感情的，易受感动的

参考例句：

• Children are more susceptible than adults.孩子比成人易受感动。
• We are all susceptible to advertising.我们都易受广告的影响。

30 mutation   

n.变化，变异，转变

参考例句：

• People who have this mutation need less sleep than others.有这种突变的人需要的睡眠比其他人少。
• So far the discussion has centered entirely around mutation in the strict sense.到目前为止，严格来讲，讨论完全集中于围绕突变问题上。

31 potent   

adj.强有力的，有权势的；有效力的

参考例句：

• The medicine had a potent effect on your disease.这药物对你的病疗效很大。
• We must account of his potent influence.我们必须考虑他的强有力的影响。

32 retooling   

v.（给…）更换工具， （给…）更换机械设备( retool的现在分词 )；改组，革新

参考例句：

• The factory is retooling to start making the new line of cars. 工厂正在重新装备以便开始制造新系列车型。 来自辞典例句
• Among her suggestions: retooling factories to focus on rebuilding America's transportation system. 她的建议包括围绕重新建设美国交通系统这个重心来重组汽车工业。 来自互联网

33 initially   

adv.最初，开始

参考例句：

• The ban was initially opposed by the US.这一禁令首先遭到美国的反对。
• Feathers initially developed from insect scales.羽毛最初由昆虫的翅瓣演化而来。

34 awareness   

n.意识，觉悟，懂事，明智

参考例句：

• There is a general awareness that smoking is harmful.人们普遍认识到吸烟有害健康。
• Environmental awareness has increased over the years.这些年来人们的环境意识增强了。

35 pelting   

微不足道的，无价值的，盛怒的

参考例句：

• The rain came pelting down. 倾盆大雨劈头盖脸地浇了下来。
• Hailstones of abuse were pelting him. 阵阵辱骂冰雹般地向他袭来。

36 painstaking   

adj.苦干的；艰苦的，费力的，刻苦的

参考例句：

• She is not very clever but she is painstaking.她并不很聪明，但肯下苦功夫。
• Through years of our painstaking efforts,we have at last achieved what we have today.大家经过多少年的努力，才取得今天的成绩。

37 isolating   

adj.孤立的，绝缘的v.使隔离( isolate的现在分词 )；将…剔出（以便看清和单独处理）；使（某物质、细胞等）分离；使离析

参考例句：

• Colour filters are not very effective in isolating narrow spectral bands. 一些滤色片不能很有效地分离狭窄的光谱带。 来自辞典例句
• This became known as the streak method for isolating bacteria. 这个方法以后就称为分离细菌的划线法。 来自辞典例句

38 analyze   

vt.分析，解析 (=analyse)

参考例句：

• We should analyze the cause and effect of this event.我们应该分析这场事变的因果。
• The teacher tried to analyze the cause of our failure.老师设法分析我们失败的原因。

39 beacon   

n.烽火，（警告用的）闪火灯，灯塔

参考例句：

• The blink of beacon could be seen for miles.灯塔的光亮在数英里之外都能看见。
• The only light over the deep black sea was the blink shone from the beacon.黑黢黢的海面上唯一的光明就只有灯塔上闪现的亮光了。

40 isolates   

v.使隔离( isolate的第三人称单数 )；将…剔出（以便看清和单独处理）；使（某物质、细胞等）分离；使离析

参考例句：

• The transformer isolates the transistors with regard to d-c bias voltage. 变压器可在两个晶体管之间隔离直流偏压。 来自辞典例句
• In regions with certain isolates of TRV, spraining is more prominent. 在具有TRV某些分离物的地区，坏死是比较显著的。 来自辞典例句

41 potency   

n. 效力，潜能

参考例句：

• Alcohol increases the drug's potency.酒精能增加这种毒品的效力。
• Sunscreen can lose its potency if left over winter in the bathroom cabinet.如果把防晒霜在盥洗室的壁橱里放一个冬天，就有可能失效。

42 lull   

v.使安静，使入睡，缓和，哄骗；n.暂停，间歇

参考例句：

• The drug put Simpson in a lull for thirty minutes.药物使辛普森安静了30分钟。
• Ground fighting flared up again after a two-week lull.经过两个星期的平静之后，地面战又突然爆发了。

43 dominant   

adj.支配的，统治的；占优势的；显性的；n.主因，要素，主要的人(或物)；显性基因

参考例句：

• The British were formerly dominant in India.英国人从前统治印度。
• She was a dominant figure in the French film industry.她在法国电影界是个举足轻重的人物。