Frexalimab

Step back from the multitude of details that go into every big pharma pipeline, and you’ll see the influence that blockbusters have on the entire field. These days, making your mark in R&D at the level the top 15 spenders play requires not just one, two or three experimental drugs that can earn a billion dollars a year. It’s typically about a slate that includes candidates that can bring in $3 billion to $5 billion a year, preferably more. The numbers keep getting bigger. When Merck execs look at the $30 billion-plus hole they have to fill once Keytruda goes off-patent, they know that anything under a billion won’t count for much. And you can see the same math dominating discussions at J&J, Pfizer, Bristol Myers Squibb and more. On the plus side, the drive to move the dial on sales includes changing standards of care for large numbers of patients. That can open up some hard targets that have defied investigators for years. The hunt for first- and best-in-class drugs inspires truly innovative development work. But for patients — including me — who suffer from diseases that aren’t among the major league targets, it can be hard to find much interest among a set of companies that have to think big in order to survive. These days, with IPOs still out of favor, the blockbuster strategy of the big cap players is more influential than ever. Those R&D alliances that can sustain a biotech will be skewed to the companies that are breaking new ground where pharma sees the biggest upsides. And it will bend an entire global industry’s decision-making process. Success breeds success in this field. AstraZeneca, which once struggled to turn around the industry’s weakest pipeline, can now devote close to $14 billion a year for drug research in a variety of fields. And that has helped alter the landscape of the R&D 15, which once was long dominated by Roche. Other key themes emerge here. One of the most important is the emergence of China as a force in drug discovery. BD teams looking for R&D shortcuts have begun picking up drug candidates in bulk in China, presenting a thorny new reality for US and European biotechs that aren’t able to move as quickly. This year, I’m concentrating on public pharma companies, which have always dominated the list. But it excludes the privately-owned Boehringer Ingelheim, where it’s harder to find details on the pipeline. Takeda also drops off this year’s list, falling just short of the dollar mark needed. And Regeneron marks its arrival as the big biotech invests heavily in its pipeline. — John Carroll The big picture: During 2023, Merck bulked up on M&A deals that pumped up its R&D budget line to a whopping $30.5 billion. In 2024, the pharma giant continued shelling out the big bucks, but without a scale-tipping deal like the $10.8 billion Prometheus acquisition we saw included in the R&D line in 2023. Nevertheless, Merck easily held on to the top spot among the 15 biggest public company R&D spenders on the planet. By the end of last year, Merck had once again dwarfed the old R&D spending leaders like Basel-based Roche, where budget discipline remains a constant. Merck has been shoveling cash into the R&D engine because it’s three years away from a titanic collision with a key patent loss for Keytruda, the $30 billion — and counting — PD-1 behemoth that went a long way to changing the way cancer is treated. Merck continues to rack up big annual increases in Keytruda revenue, which has been essential as the company’s other big earner — Gardasil — fizzled in the face of some ambitious sales projections for the China market. There’s one ace in the hole, with analysts arguing over just how much Merck can make from their late-stage subcutaneous version of Keytruda, which will come with a whole new patent life to profit off of. But whether it’s $6 billion or $7 billion a year, that still leaves a Grand Canyon-sized gap in the budget that must be filled. And the rep of CEO Rob Davis and R&D chief Dean Li will be made or lost on their pipeline strategy for a Keytruda replacement. Or replacements. “The future is less monolithic Keytruda,” Davis said . “It’s going to be a lot of smaller, precision-based therapies aimed at specific tumors or indications.” It’s going to take a lot of smaller drugs to mend a rip that size. That means a long string of deals, including a move to elbow its way to the future of immunotherapy with a rival to Summit’s PD-1/VEGF combo. And that required a turn to China, following what is now a well-beaten path for new drugs that they’ve bet big on. Merck kept the focus on China when it inked a deal just days ago for an oral Lp(a) inhibitor from Hengrui . Novartis recently delayed the timeline for wrapping its Phase 3 study for an antisense candidate for Lp(a) (partnered with Ionis), pushing the results for data on 8,000 patients to the first half of 2026. Merck put up a $200 million down payment on a $2 billion deal for an oral treatment that will need to go through a global program. That’s a low-cost deal in front of a major trial expense, and it offers a chance to leap into a race where orals may well end up ruling the franchise. But it’s no Keytruda. Investors don’t care much for the overall picture. Merck’s shares have dwindled more than 21% over the past year, even as sales kept climbing. Wall Street wasn’t crazy about Merck’s decision to withdraw guidance on Gardasil, at all. And the Keytruda dilemma has created a narrative that has dominated the company for years now. Merck execs can project confidence, but R&D spending illustrates a high level of anxiety. The big picture: You can bet that Roche execs were paying particularly close attention to AstraZeneca’s recent release of a positive, preliminary slice of late-stage data for camizestrant, its oral SERD for hormone receptor-positive, HER2-negative breast cancer. The Basel-based pharma giant has been angling — alongside Eli Lilly — to beat a path to the market with a best-in-class oral SERD that can be expected to rack up billions a year, provided they get in early on a field that has been a primary concern for years. Roche CEO Thomas Schinecker has pegged giredestrant as one of its top late-stage drugs, putting it in the pole position of a chart of potential blockbusters as it waits for late-stage data from their persevERA and evERA trials. It’s in a group of seven pipeline therapies that Roche believes can pave the way to new franchises worth $3 billion or more. AstraZeneca has pegged its rival as a $5 billion-plus earner, offering some added insight here on where the market is focused. But the others include some high flyers that face daunting odds in the clinic, as well as a cluster of rivals that Roche has to race for best-in-class status. Take, for example, the amyloid buster trontinemab, which recently offered an early picture of its ability to target the plaque — cognition was not part of that study, though. And the road for Alzheimer’s drugs is long and frequently twisted, with a questionable marketing future if it fails to do more than slow progression. Prasinezumab has failed a couple of mid-stage studies for Parkinson’s, as investigators try to find a population where it works. Parkinson’s remains one of the toughest targets in the industry, with repeated setbacks for key players — including a rival with the mechanism as Roche’s drug. Trontinemab and prasinezumab are both up for Phase 3 enabling readouts this year. Astegolimab is a dark horse Phase 3 candidate in a group of drugs aimed at taking on Dupixent’s dominant role in COPD. That drug — which inhibits the IL-33 receptor ST2 — was flagged for pivotal readouts this year from the ALIENTO and ARNASA trials. A couple of years ago, Roche fronted $310 million to partner with Alnylam on the RNAi drug zilebesiran for hypertension, which has posted positive mid-stage data. That makes the cut as a major potential player. NXT007 offers a new shot at hemophilia A after Roche took a hit on its gene therapy out of the Spark buyout. Long term, Roche wants to keep building around the Hemlibra franchise, which brought in $5 billion in 2024. In the follow-up category of potential blockbusters, Roche counts four drugs with $2 billion to $3 billion in peak sales potential. That group includes their BTK inhibitor fenebrutinib, which has reportedly done well in Phase 2 for MS. That’s up for a pivotal readout this year, along with vamikibart, which is in two studies called SANDCAT and MEERKAT for uveitic macular edema. As one of the biggest R&D operators in the world, Roche can afford a big pipeline with a number of misses. It’s the one or two big successes in each group of contenders that sustain a company of this size, as it proved yet again with their Regeneron rival Vabysmo, which broke through the $4 billion barrier last year as Tecentriq flattened out and exhibited signs of erosion. Polivy also jumped into the blockbuster club, marking a key marketing success. The key thing for Roche R&D is putting up a slate of credible contenders, with a group of late-stage candidates tackling big diseases and at least one big prospect that looks competitive in the multibillion-dollar class. To that end, Roche continues to selectively snap up new candidates and forge new alliances around the globe. In recent months we’ve tracked an antibody pact with UK biotech Oxford BioTherapeutics, heavily weighted to biobucks as is common in discovery deals. And they went back to the China well for a new deal with Innovent on small cell lung cancer that cost $80 million in upfront cash. Paying $1 billion for the off-the-shelf CAR-T tech at Poseida amounted to a small bolt-on in this world. Roche paid $2.7 billion for Carmot, and had some positive early data to exhibit last year. A lot of this will sour or fizzle out. TIGIT was once a hot prospect, but it’s all been bad news on that front. You win some, you lose some in Big Pharma. Roche has been winning enough to stay on top, but the pressure is always on. The big picture: Pascal Soriot took plenty of painful shots during his early years as CEO of a woeful AstraZeneca — including more than a couple from me — with each setback cause for fresh concern. Slowly building a slate of giant franchises in oncology, and buying Alexion to beef up earnings, ended the fretting. By the end of 2024, AstraZeneca’s top execs could boast of full-year revenue growth of 21%. Industry buzz has Soriot spending big chunks of every year in China, where the company has been working to make a confrontation with the government into a commercial speed bump, hoping to continue to romp and stomp while using its international status and UK headquarters to steer clear of the showdown between the US and China. And it recently underscored the connection by unveiling plans for an expansion of its R&D work in China. Its growing commercial success with proven oncology drugs has spurred Soriot to invest heavily in the pipeline, stretching past cancer into other fields, like obesity. Five years ago, AstraZeneca shelled out $6 billion for R&D in 2019. In 2024, that tally had more than doubled as AstraZeneca surged from a cash-strapped player to an industry leader in research, trailing only Merck as the US outfit urgently tries to engineer a replacement set of drugs for an aging Keytruda franchise. Quite a few analysts are ready to offer their thumbs-up for AstraZeneca’s progress, but the question now is likely to center on whether AstraZeneca can keep its winning streak on track. Case in point: Camizestrant has been built into a $5 billion+ annual prospect. Some observers are ready to sign off on a blockbuster future for the oral SERD drug, especially after a recent Phase 3 win, but temper the enthusiasm with somewhat lower sales expectations. Baxdrostat also gets star billing, as Soriot touts “more than 90 late-stage trials underway with an average non-risk adjusted peak year revenue per trial of $1 billion.” The focus now is on performance in the clinic, but AstraZeneca’s financial results give it considerable range to consider more deals. Soriot picked up baxdrostat — exploring a new mechanism of action for hypertension that investigators have been exploring for close to 20 years — in a $1.8 billion deal for CinCor two years ago. And the pharma giant has helped blaze the BD path through China, leaving it in a position to scoop up fresh assets at discount prices. R&D risk is always huge, but investors have liked the odds. $AZN is up 16% over the past year. The big picture: With biosimilar competition ramping up this year for Stelara, one of J&J’s mainstay mega-franchises ($10.4 billion in 2024), the pharma giant needs to rack up some regulatory wins from the late-stage pipeline. The company’s R&D group breathed a sigh of relief when icotrokinra, its big program for IBD brought in from Protagonist, recently delivered — at least on the major points we could see in the company statement — in an important mid-stage trial of the oral IL-23 therapy. J&J execs, who have been slowly unfolding a pipeline-in-a-product strategy for this drug, believe icotrokinra can be a $5 billion-a-year earner, putting it at the tip of the big phalanx of R&D projects now in the pipeline. Another late-stage drug that gets a lot of attention at J&J is nipocalimab for generalized myasthenia gravis, which has nabbed breakthrough drug status at the FDA as it looks for an OK. And there’s a new fast-track designation for this drug in moderate-to-severe Sjögren’s disease. J&J is a behemoth with a long list of marketed drugs, a fact that comforts risk-averse investors. But the churn tends to deter anyone looking for some quick upside. Its medtech group spent $3.7 billion on R&D last year, helping maintain a stable of products that deliver on the bottom line. That helps keep the numbers steady. And it helps when one-time blockbusters-to-be — I’m talking about aticaprant here — flounders in its Phase 3. J&J had slated the anti-depressant in the $1 billion to $5 billion category, up until a few weeks ago when the drug giant wrote it off for insufficient efficacy. Anyone who’s been following depression R&D for the past 20 years wouldn’t have been too surprised to see yet another Phase 3 fail here. But neuro is still surging on increased confidence that scientists can deliver major drugs for unmet needs. For J&J, the belief helped inspire the Intra-Cellular Therapies buyout for $14.6 billion during JPM, finally breaking the year-plus drought of M&A deals that broke the $5 billion barrier. That deal, like the top drugs in its pipeline, underscores a well-known fact about J&J. The company is a global player in R&D — helping break the mold on China deals when it picked up the cancer drug Carvykti. But while the company can be a world-class drug picker, it’s not known for discovery work. J&J has also long been operating under a cloud brought on by its talc settlement talks, where the numbers people have set aside billions and appear to be close to finally completing a deal to shunt talc into a subsidiary and settle up with the bulk of the lawsuits. It’s manageable, but after 16 years and thousands of suits, J&J’s investors would like to move on. Following its spinout of the consumer division, J&J is on an R&D path — sticking with diseases its researchers understand well — it’s likely to follow for years. And that will keep BD busy. The big picture: AbbVie’s story in recent years has centered primarily around its fierce development and then commercialization of Rinvoq and Skyrizi to bridge its way past the revenue gorge created by Humira’s slow-motion loss of exclusivity. Once the biggest drug in the world, Humira is being steadily eclipsed by biosimilars, but the R&D group has kept the ball rolling with new studies to expand their pair of cash cows. The Botox buyout remains another key storyline as AbbVie proves yet again that it has an excellent set of marketing skills. Mission accomplished on the big moves, which isn’t to be underestimated. That may not add up to be the most exciting R&D story in biopharma in 2025, but it has certainly kept investors happy as AbbVie worked through a top-level executive transition and began to try kickstarting some fresh enthusiasm with a few ambitious deals. AbbVie took a major stab at neuroscience when it bought out Cerevel a couple of years ago for $8.7 billion , landing a lead asset in the field. But that strategy largely came a cropper recently with the failure of emraclidine, once intended to help change the standard for treating schizophrenia. Big Pharma has been making a few careful moves in neuro, but the unknowns are still legion, and the risks are extremely high. Roche’s setback on prasinezumab for Parkinson’s in late 2024 underscored that universal truth. AbbVie is still talking up the prospects of tavapadon as it racks up Phase 3 wins, but the upside isn’t as great, as far as the analysts are concerned. AbbVie was a late arrival to the obesity scene, talking up its potential for less frequent dosing and relatively competitive weight loss data with Gubra’s amylin drug. The BD team brought that in for $350 million upfront. There are some ADCs that the R&D group thinks highly of and a host of low-cost early-stage deals intended to raise its prospects for the future. For now, though, AbbVie is clearly relying on its marketing muscle and experienced research groups to keep building key franchises — which it is really, really good at. The jury’s out on whether AbbVie can add some major new franchises to grow the company faster. But they have time now. The big picture: Every time a CEO or biotech investor starts making the case for more M&A, often on background, they inevitably point to Bristol Myers as the poster child for Big Pharma pipeline demand. It faces huge looming patent losses — let’s start with Opdivo — and has a couple of years to wait for the kind of registrational data needed for its most promising late-stage drugs. The pharma giant has certainly been a player in the M&A club, snapping up Karuna ( $14 billion ), RayzeBio ( $4.1 billion for a radiopharmaceutical drug in a hotly contested arena) and Mirati ( $5.8 billion for KRAS) along the way. But recent moves aimed at cutting costs while boosting work in Phase 3 underscore just how tricky this can be. And all the buzz about its need for pricey buyouts hummed right along through a muted year of dealmaking in 2024. By all accounts, a few analysts on the Street seem satisfied that Cobenfy — out of Karuna — is on track to a blockbuster future, starting with schizophrenia and potentially expanding into Alzheimer’s. But its launch late last year didn’t come close to satisfying the skeptics rooting for more BD — which has been encouraged by a set of execs ready and willing to talk up their expectations on the acquisitions side of the business. Among the drugs in late-stage work, you’ll find new multiple myeloma therapies, which Samit Hirawat talked up in the last quarterly run-down. “ … It is very important to continue to develop small molecules, which are easy to deliver and can be combined with the standard of care therapies. And that’s exactly where iberdomide, mezigdomide sit,” he added, highlighting head-to-heads with pomalidomide (Pomalyst) — facing near-term generic competition — and Revlimid — already losing ground to copycats. Overall, costs have been headed up in R&D at Bristol Myers, and with all hands on deck for a Phase 3 revival of the portfolio, the pharma giant is poised to keep pouring money into drug development. The big picture: The CEO/R&D chief duo of David Ricks and Daniel Skovronsky took home the big prize with the successful launch of the drug juggernaut Zepbound/Mounjaro, which has emerged as the leading obesity/type 2 diabetes treatment in a world hungry for effective fat busters. They aced the main prize in the GLP-1+ field with their own particular take, and they are following up with additional studies to prove efficacy where it can gain reimbursements — while following up with an oral that is aimed at cementing this category in its favor for years to come. That storyline has proved enormously persuasive with investors, as Eli Lilly’s share price has grown 64% over the past two years and its biggest supporters among the analysts glow with enormous projections. But with that much money on the table, it’s no major surprise to see Novo Nordisk double down on its own obesity franchise — a story that’s had a few problems — while the competition aims at doing it better with fewer side effects and a more appealing form of administration has grown into a mob of biopharma companies. It does make you wonder where peak obesity lies. But Lilly is determined to hold onto the lead, no matter how rough this ride may get. And it promises to pay off in the tens of billions per year. To that end is a prospective 2026 launch of orforglipron, an oral GLP-1. Analysts have been on high alert for upcoming T2 data, which Lilly forecasts should look good in comparison to Novo’s semaglutide. That’s the key competitive number they’re looking for. There’s also the multi-targeted retatrutide in the pipeline to consider, where investigators tracked a 12% weight loss in a mid-stage study. Novo certainly has, inking a deal with China’s United Laboratories for an early-stage rival treatment as it looks to be competitive in a range of targets aside from GLP-1. That deal also underscores how Big Pharma can steal a march on a rival drug by scouting R&D programs in China. There’s also remternetug for Alzheimer’s, a quarterly injection to remove amyloid plaque, versus the monthly injection their approved drug donanemab (Kisunla) uses. Analysts once projected billions in upside for the new Alzheimer’s drugs making their way into the market, but skeptics wonder if their modest benefits for patients will win doctors and large numbers of patients over. Lilly’s late-stage cardio drug lepodisiran often earns a mention from leadership, along with their oral follow-up muvalaplin. Then there’s the KRAS contender olomorasib. Add in the occasional buyout — like Morphic — and you’ll get a picture of an ambitious pipeline funded with growing revenue from an effectively marketed drug with the kind of legs that can sustain a company like this for years to come. Given the company’s credibility in drug development, you’re likely to agree that Eli Lilly should never be underestimated. The big picture: By the end of 2022, Pfizer’s rep was pure gold. There was a king’s ransom in revenue for the multinational operation as it capitalized big time on its rapidly successful alliance with BioNTech for their mega-franchise mRNA vaccine to combat Covid. And CEO Albert Bourla basked in the glow of accolades for helping save the world — with the exception of some stray trolls. Then the world turned, vaccine demand plummeted far past most projections and Pfizer was left to pick up the pieces with a revised R&D game plan and revenue that only modestly improved in 2024 after bottoming out at $59.5 billion in ’23. Now, instead of continuing accolades for a truly historic vaccine rollout, analysts were reminded of Pfizer’s long track record for hit-and-miss performance in R&D and commercial ops. And it remains a big player in vaccines, where the long reach of the new Trump administration and its vaccine critics has extended to scrubbing out references to mRNA. Those persistent doubts led Pfizer to recruit Citi analyst — and longtime Pfizer doubter — Andrew Baum to help sell the company’s innovation plans. And he likely is more aware than most of just how hard that is as Pfizer looks to largely tread water on the numbers side this year. Buying Seagen set its course for a higher profile in oncology, which was on display as Bourla cheered their late-stage programs in his recent assessment of what’s ahead. Bourla earlier tapped oncology chief Chris Boshoff to take over R&D from Mikael Dolsten, signaling that it’s relying on a slate of cancer drugs to help replace Ibrance and Xtandi as those big blockbusters lose exclusivity in a couple of years — mere ticks of the clock in drug development cycles. So it’s no surprise to see company execs talking up prospects for the CDK4 inhibitor atirmociclib, now in a Phase 3 breast cancer study. But they took a nasty hit a few weeks ago when vepdegestrant, its protein degrader partnered with Arvinas, fell short in another breast cancer study. Baum also has his work cut out for him talking up Pfizer’s big plans for their oral obesity drug danuglipron, with analysts shaking their heads over a twice-daily dosing as rivals make progress on that front with drugs that may be much better positioned. Its cachexia drug ponsegromab, meanwhile, has had its late-stage development plan trimmed. Underscoring the doubts about Pfizer, analysts haven’t liked watching its sales of RSV vaccine Abrysvo plunge in a turbulent market for everyone involved. The pharma player has to perform consistently on sales if it expects to overcome the skeptics at this point. Add it all up and Pfizer looks like it will continue to operate under a cloud for some time to come, needing to establish a solid track record of significant new approvals and reliable marketing success. In the meantime, look for the company to keep shelling out big dividends to keep investors happy. The big picture: Under the watchful eye of chairman Joerg Reinhardt, Novartis CEO Vas Narasimhan has always proved ready to bring out the scalpel — or the axe — to trim away at its enormous global structure. So no analyst would have been surprised to see Novartis cutting away at its commercial ops in anticipation of a looming patent loss for its heavyweight therapy Entresto. A cliff like that would make many pharmas amp up R&D spending in a big way. Novartis actually cut back in 2024. The other Basel-based pharma giant is playing this one carefully for Wall Street, defending what’s left of patent exclusivity while signaling an LOE for Entresto in the middle of the year. It’s boosted revenue from Entresto in advance of the inevitable decline of its star drug — like pumping money from a dying well — and it’s pushing its other portfolio drugs hard, looking to make up for its blockbuster losses. That push includes building the franchises for Fabhalta, which just won its third approval, along with other drugs like Leqvio and Scemblix. Novartis has maintained a big focus in R&D on its radioligand portfolio, along with cell and gene therapies and RNA. Its late-stage pipeline includes OAV101 IT for spinal muscular atrophy, using a new delivery method aimed at widening the patient population for Zolgensma and now lining up for regulatory approvals. And there’s a big emphasis on votoplam (PTC518) for Huntington’s, in-licensed from PTC. Earlier this year Narasimhan and his execs spent a fair amount of time talking up the prospects of votoplam, which has to complete a mid-stage program successfully before Novartis takes over Phase 3. Huntington’s is wide open for anyone who can move the bar on this fatal neurodegenerative disease. But it’s also incredibly difficult to master, as Novartis knows from its own recent failure in the field with branaplam. Sage has also hit the wall here. But Novartis feels it’s learned a lot from its own setback — enough to believe that they can take the command here. Novartis, despite a busy pipeline overall, has a pretty thin set of late-stage drugs to tout, which led the Wall Street Journal to ask where Narasimhan expects to get its next round of drugs as Novartis sets out to perform with annual revenue increases in the mid-single digit range. Novartis spent a billion in cash on its Huntington’s alliance, underscoring just how careful they are with the R&D budget, which fell year-over-year in 2024. Not surprisingly, he centered on “smaller deals” while insisting he won’t make a move in obesity unless the BD team can line up something particularly distinctive. He also counts himself happy with their 2022/2023 reorganization. Happy, though, doesn’t mean content to leave things be. Novartis is always turning over stones to see where else it can cut. It adds up. And it’s shown zero interest in doing anything splashy. Its recent buyouts underscore that careful approach: MorphoSys was on the outer edge of the $1 billion to $3 billion range where Novartis prefers to play in M&A. At Novartis, financial discipline is a core value. And it’s part of the buttoned-down Swiss approach that isn’t expected to change. The big picture: There are a lot of moving parts at GSK, and not all are headed in the right direction. Its RSV vaccine sales have been on a roller coaster ride. The UK pharma’s big bet on Shingrix was dinged by slipping sales last quarter, all while the Trump administration helped cast a pall over vaccines in general that may well endure for four years. The vaccine market in China has also been wobbly, as Merck can attest to with Gardasil. On the other hand, GSK once again has high hopes for Blenrep, which was yanked from the market in 2022 after flunking a confirmatory study. The IL-5 therapy depemokimab has excited great expectations for £3 billion in annual sales, following up on the success of their asthma drug Nucala. All the while the BD group keeps turning up new deals that bolster their case without weighing heavily on the numbers side. And CEO Emma Walmsley, now an eight-year veteran in the top spot, is promising to move its top line to $50 billion, moving from £31.4 billion last year to 40 billion — a 27% increase in seven years. A lot of that increase will depend on how GSK’s commercial arm can capitalize on new therapeutics like their newly approved antibiotic gepotidacin. Commercial chief Luke Miels has cited analysts’ estimates for up to $1.25 billion for that program, but not everyone is nearly that enthusiastic about the near-term chances for a new antibiotic that could take years to gain a firm footing in the market. GSK has never been flashy. The stock is down about 10% over the past year. If you pull back over a three-year timeline, since GSK spun off its commercial group, the stock is down 19%, all of which has some analysts wondering if the large-cap company may once again become a target of the activist crowd. The big picture: I met Paul Hudson in Paris five years ago, when he stepped in as the new Sanofi CEO after a lengthy dry spell in R&D. Since then, he’s proven time and again that he’s ready and willing to invest in drug research, despite the inevitable ups and downs associated with bigger pipelines. A bit more than two years ago he was concentrating on what he called three major blockbuster candidates (€5 billion-plus): The OX40 drug amlitelimab, frexalimab and SAR441566, an oral TNFR1. And he was ready to sacrifice some profitability to move a pipeline where he counted another nine blockbuster candidates, mostly in immunology and inflammation. He kept that promise, with a boost in R&D spending of 14% in 2024 as Sanofi joined the industry migration out of consumer — staking its future on its ability to push new drugs to big futures. A few days ago Leerink noted that Sanofi was still juggling OX40 drugs to see whether amlitelimab, or its OX40L/TNF bispecific nanobody, would go into Phase 3 for hidradenitis suppurativa. That drug is in Phase 3 in atopic dermatitis and in Phase 2 in asthma and several other indications. Frexalimab failed a Phase 2 for Sjögren’s syndrome last year, narrowing its potential. That came with a Phase 3 failure of venglustat — another one of Hudson’s original top prospects — which nicked off part of its attraction as well. The next tier, where Hudson forecasts sales of €2 billion to €5 billion includes: Sanofi had one huge ace in the hole when Hudson took over the hand. It could rely on big sales of Dupixent ($13 billion in global sales last year) to keep it going in search of a new portfolio. And their marketing expertise in the field — built thanks to their alliance with Regeneron, which did the heavy lifting on the innovation side — would benefit any new drugs to warrant a regulatory approval while easing Aubagio out as generics took hold. The big picture: After hustling its way to the front of the GLP-1 line, Novo Nordisk is now all about the fierce rivalry it’s facing from Eli Lilly while positioning itself against any other entries that could sap its brilliant future in obesity. And that is no easy task, as execs have learned over the past year, while its stock plummeted 45% after peaking out as an obesity darling last summer. It turns out that superheating the stock price set up a supercooling series of events. After seeing explosive growth in revenue last year, Novo’s executive team is counseling analysts about a more modest growth path in 2025 as Eli Lilly brings the heat and pricing pressure grows. One of the big jobs they had to complete ASAP was being able to make enough semaglutide to satisfy the market and get off the drug shortage list — battling back against compounders who were carving up market share. While Novo Nordisk hasn’t been keeping up with average R&D spend among the top 15 — which generally comes in around the low 20s as a percentage of revenue — even 16.5% allowed for a 50% hike in R&D spending last year. In recent weeks Novo not only reorganized its growing R&D ops, it also struck back-to-back deals for new obesity drugs in an effort to stay ahead of the mob out to grab a share of the action. Now diabetes/obesity/MASH will be one R&D cluster focus, with cardio/chronic kidney disease and rare diseases making up the other two legs of its three-pronged research strategy. And like every other company in the R&D 15, it will rely on AI to make better bets on experimental drugs. Normally, that might make an intriguing proposition for investors, but analysts have been more focused on repeated setbacks in the clinic than the prospective benefits of a revised strategy. Novo Nordisk recently aired lackluster data for CagriSema, its follow-up drug that is a combination of the amylin analog cagrilintide and GLP-1. One of the big downsides to GLP-1 is the side effects of the drug, which the amylin analog is thought to limit while building weight loss. But it barely edged a high dose of Zepbound, leaving Lilly in the lead of the expectations game. And it earlier fell far short of the company’s stated expectation that it could trigger 25% weight loss. There’s lots more on the way, but Novo Nordisk has a lot riding on a head-to-head between CagriSema and Zepbound. Those data will come later this year, and failure is not an option. The big picture: Amgen has added a meaningful amount to its R&D budget, but it’s still hanging on in the second tier of the R&D 15. As always with CEO Bob Bradway, there’s a well-thought-out strategy that he’s pursuing — and selling to investors as the best path forward. And as always, the stakes are incredibly high. While looking to build on some existing drug franchises, Bradway once again used his Q4/2024 call with analysts to put the spotlight squarely on Amgen’s top prospect in the pipeline. This year it’s MariTide, an obesity drug that is looking to find a patch of marketing sun in the Big Kahuna of all drug rivalries. But it’s one tough sale. A few months ago, in a story covered by Max Bayer at Endpoints News , Amgen saw its stock take a dive on positive mid-stage data that illustrated a 20% weight loss for the drug. Once upon a time, you could have parlayed that into star status on Wall Street. But no more. It looked a little second-rate compared to the megablockbuster leaders in obesity, Novo Nordisk and a romping, stomping Eli Lilly, even if it can be effective at lower dosing. Amgen has a new take on the glucose-dependent insulinotropic polypeptide (GIP) receptor, blocking it instead of activating it. But it may just be the amped-up GLP-1 component that is delivering the benefit. Amgen has a huge Phase 3 for this one to answer all its questions, but you can see a few analysts are taking to the sidelines on this one, not quite won over by the dosing and design. On the upside: Any significant piece of obesity can be huge, even if in this case it’s relatively small compared to the leaders’ market share. On the downside: A big lead counts for a lot when you’re breaking new ground in therapeutic research, and Amgen definitely does not have the lead here. Amgen, though, will stick to its story. While it’s far from the top 10 in terms of R&D spending, the company has always punched above its weight when it comes to touting an experimental drug. So it was no surprise to see ex-Novartis vet Jay Bradner pick up his first Q4 call at Amgen by keeping his sights set on MariTide. But Bradner is also quick to highlight other late-stage prospects, topped by its Lp(a) drug olpasiran — now one of several drugs in the mix for this target — while waiting on the FDA decision for Uplizna. There’s also the Phase 3 program for rocatinlimab in atopic dermatitis, which has the potential to pursue other pathways, provided the data are strong. That could prove a major caveat, though, While Tim Anderson sees Amgen as 12 to 18 months ahead of Sanofi’s rival OX40 mab amlitelimab, he called one of the mid-stage data cuts “underwhelming” compared to Dupixent, hampered by some safety concerns. The big picture: Gilead has been anchored by HIV for years now, able to take multiple hits on the R&D side without triggering too much angst among investors. And Gilead CEO Daniel O’Day — who celebrated six years in the top post — has been winning over some mild converts to the cause recently, including Tim Anderson. Anderson, like the rank-and-file investor group, is comforted by Biktarvy’s big role in the HIV arena, where Gilead mints money. And he’s intrigued by the upside of a couple of late-stage plays, including anito-cel, which Gilead — partnered with Arcellx — believes can cut down Carvykti from J&J and Legend. That depends a lot on the safety profile that has been emerging in clinical trials. But at this stage, Gilead has seen a slate of oncology prospects go down in flames, which hasn’t done much to increase confidence in a cancer drug now. On the other hand, maybe they are due for a win. If they can cut into line with Carvykti, which is linked with Parkinson’s and other serious side effects, it has the potential to earn billions. And that would push them to their goal of getting 30% of revenue from oncology, rather than continue to rely so heavily on its longtime dominance in HIV. But there are some big ifs along the way, including the developers’ plans to look for an accelerated approval of the CAR-T. The big picture: Regeneron was close to making the R&D 15 in 2023, and it made it through last year with a surge of research spending in 2024 that slipped ahead of Takeda, based on their last four quarters. Regeneron arrives as the only company that still counters its two remarkable founders in the top posts: Science chief George Yancopoulos and CEO Len Schleifer. They got to this point by creating a company that is frequently held up as the gold standard of biotech startups, building two giant franchises in Dupixent (partnered with Sanofi) and Eylea. Now Eylea has biosimilar trouble, but Dupixent is still romping and stomping on the numbers side, giving Regeneron a nice runway to build new drugs. Tim Anderson at Bank of America counts two key drugs in the late-stage pipeline, and one to watch now in Phase 2. There’s fianlimab, a LAG3 treatment in frontline melanoma that hasn’t received a ton of attention. Anderson notes that Regeneron is several years behind Bristol Myers in LAG3, with 2030 sales set under the $900 million mark. LAG3 has had a number of problems in the clinic, though, and the jury is definitely out on what the potential is here. And there’s IL-33 mAB itepekimab, also partnered with Sanofi. Not the next-gen successor to Dupixent as once billed, Anderson still sees blockbuster potential. Then there’s trevogrumab — an anti-myostatin — and the anti-activin A garetosmab for obesity, in Phase 2 development with a host of rivals in the clinic. Of more immediate importance commercially, Regeneron has tagged linvoseltamab , its BCMAxCD3 drug delayed for manufacturing reasons, as a likely near-term entry for multiple myeloma. Sales projections are relatively muted, though. There’s also a CRISPR drug partnered with Intellia, NTLA-2001 for ATTR amyloidosis . Of everyone on the R&D 15, Regeneron is reinvesting a larger percentage of its revenue than any other player. Thirty-seven years after the biotech was created, the founders still see themselves on the cutting edge of drug research.

1 仁域 CD40/CD40L靶点概述 1 CD40的分子结构：CD40是I型膜糖蛋白，基因位于染色体20q11-13，属于肿瘤坏死因子受体(TNFR)超家族的共刺激成员，需形成三聚体来实现最佳信号传导。在人类中，它有62个氨基酸的胞质尾、22个氨基酸的跨膜结构域和173个氨基酸的胞外结构域，胞外结构域含有4个半胱氨酸富集域(CRDs)，可参与寡聚化和配体结合。存在膜结合型(mCD40)和可溶性(sCD40)两种形式。sCD40能够作为CD40的天然拮抗剂，通过干扰CD40/CD40L的相互作用发挥作用。 图1 CD40及其配体CD40L的结构域结构 2 CD40L的分子结构：CD40L是II型膜糖蛋白，又名CD154，位于X染色体Xq26.3，属于肿瘤坏死因子超家族(TNFSF)。在人类中，包含22个氨基酸的胞质尾、24个氨基酸的跨膜结构域和215个氨基酸的胞外结构域，胞外区有保守的TNF同源域，这一结构域使其能实现三聚化并与受体结合。同样存在膜结合型(mCD40L)和可溶性(sCD40L)两种形式，以非共价结合的同源三聚体发挥生物学活性。mCD40L可促进肿瘤消除，sCD40L则抑制免疫反应、阻碍细胞凋亡、促进肿瘤血管生成。此外，CD154还能与αIIbβ3、αMβ2、α5β1等多种整合素家族成员结合。 表1 CD40/CD40L的结构及分类 3 CD40/CD40L的相互作用：CD40/CD40L的结合位点位于CD40L三聚体的亚基间凹槽，结合界面存在电荷互补，对下游信号传导至关重要。 图2 CD40/CD40L检查点分子加工和相互作用 4 CD40/CD40L的氨基酸序列 Extracellular Helical Cytoplasmic 21-193 194-215 216-277 CD40:MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ Extracellular Helical Cytoplasmic 47-261 23-46 1-22 CD40L:MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL 2 仁域 CD40/CD40L的表达与调控 1 CD40的表达与调控：在免疫和非免疫细胞上均有表达，其表达受多种转录因子调控，在不同细胞中的表达各异，在B细胞和髓系细胞中CD40表达相对较高。“危险”信号（如病原体相关分子模式、损伤相关分子模式）及炎症细胞因子（如粒细胞/巨噬细胞集落刺激因子、白细胞介素-3和干扰素-γ等）等可提升mCD40的表达水平。 2 CD40L的表达与调控：CD40L在T细胞和血小板中表达较高。静息CD4⁺T细胞几乎检测不到mCD40L，而激活后的CD4⁺T细胞会高表达mCD40L，且其表达受多种机制严格调控。在血小板中，静息时无mCD40L表达，受到刺激后，mCD40L会快速且短暂地表达。此外，mCD40L在其他免疫细胞（如CD8⁺T细胞、肥大细胞、嗜碱性粒细胞等）以及条件先天免疫细胞（如内皮细胞、血管平滑肌细胞等）中也可诱导表达。 图3 原代人细胞中的 CD40 和 CD40L 表达谱 3 CD40/CD40L的细胞内信号传导：CD40信号主要经通过招募肿瘤坏死因子受体相关因子(TRAF)家族成员以细胞类型和刺激依赖性方式介导，不同TRAF成员与CD40结合，激活不同信号通路。这些信号通路包括NF-κB、MAPK、PI3K/AKT、JAK3/STAT等，进而调节细胞的增殖、分化、凋亡等过程。 图4 CD40/CD40L信号通路 3 仁域 CD40/CD40L相互作用的效应功能 1 对免疫细胞的作用：CD40在多种免疫细胞上表达，其激活对不同免疫细胞有不同影响。促进B细胞增殖、分化、产生抗体；激活髓系细胞，增强抗菌活性；促进树突细胞(DCs)的激活与成熟；调节T细胞分化、激活和记忆维持；促进血小板激活和聚集；促进巨噬细胞从M2型向M1型转化，分泌细胞因子；促进中性粒细胞的激活和脱颗粒。 图5 CD40刺激对肿瘤微环境中免疫细胞的影响 2 CD40/CD40L的病理功能 免疫调节作用：调节免疫反应和炎症，促进T细胞与B细胞相互作用，激活抗原呈递细胞，启动适应性免疫反应，影响肿瘤微环境和癌症进展。 炎症反应中的作用：诱导促炎细胞因子生成，激活内皮细胞，促进白细胞募集和炎症驱动的血管生成，还可激活细胞内信号通路，促进抗肿瘤免疫反应。 与肿瘤细胞的相互作用：激活抗原呈递细胞，增强肿瘤细胞MHC分子表达，促进免疫原性细胞死亡，增加肿瘤细胞对T细胞裂解的敏感性，调节肿瘤相关巨噬细胞表型，在不同癌症中发挥不同作用。此外，二者结合后可激活APC，促进生发中心形成、抗体类别转换等。 图6 CD40/CD40L相互作用的效应功能 3 对肿瘤细胞的两面性：CD40/CD40L相互作用在肿瘤细胞中的作用具有两面性。一方面，在B细胞恶性肿瘤（如非霍奇金淋巴瘤、慢性淋巴细胞白血病、多发性骨髓瘤）中，它可促进肿瘤细胞增殖、抑制凋亡，上调促炎细胞因子和共刺激分子，增强T细胞启动；另一方面，它也能诱导某些肿瘤细胞（如恶性B细胞、乳腺癌、肾细胞癌等）生长停滞和凋亡，这主要取决于肿瘤细胞类型和免疫微环境。 4 仁域 CD40/CD40L靶向治疗 图7 CD40/CD40L靶向治疗的策略和机制 1 激动剂疗法：主要用于肿瘤免疫治疗和疫苗佐剂。通过增强CD40/CD40L信号激活免疫细胞、诱导肿瘤细胞凋亡，已在多种恶性肿瘤早期临床试验中进行评估。在抗肿瘤治疗中疗效相对较低，完全缓解率为2%-20%，部分缓解率为4%-28.6%，且单药治疗效果不佳，存在剂量限制性副作用，如肝损伤、细胞因子释放综合征等。 表2 CD40激动剂治疗的临床试验 表3 CD40L激动剂治疗的临床试验 2 拮抗剂疗法：主要用于器官移植和自身免疫病治疗。阻断CD40/CD40L相互作用，抑制免疫细胞激活，用于治疗自身免疫性疾病和B细胞恶性肿瘤。在自身免疫性疾病治疗中，临床反应率为46%-75%，展现出一定的前景，阻断CD40/CD40L通路理论上可调节免疫反应，减少自身抗体产生和组织损伤。但在临床试验中，第一代药物出现了血栓栓塞或免疫抑制等严重副作用，第二代药物安全性有所提升。 表4 CD40拮抗剂治疗的临床试验 表5 CD40L拮抗剂治疗的临床试验 3 双特异性CD40抗体 ①靶向肿瘤相关抗原(TAA)的双抗可增强疗效并实现安全给药。 ②靶向CD47的双抗能阻断“别吃我”信号，增强抗肿瘤效果。 ③靶向PD-L1的双抗因CD40结合导致的短半衰期，在维持PD-L1受体持续占位上存在挑战。 ④靶向肿瘤基质蛋白的双抗可定向激活TME中的免疫细胞，但无法像TAA靶向双抗那样促进肿瘤特异性T细胞的交叉启动。 ⑤靶向T细胞受体的双抗能重新激活肿瘤特异性T细胞，部分药物已进入临床试验阶段。 图8 基于第二个靶点性质的不同类别的双特异性CD40抗体 4 其他CD40靶向方式：CD40靶向疫苗可增强抗原呈递，激发T细胞反应，部分处于研发阶段；CD40靶向纳米颗粒能改善癌症疫苗递送和疗效；基于基因疗法的CD40刺激，使用不同病毒递送系统，在临床前和临床试验中均展现出一定潜力。 表6 基于CD40配体的新兴靶向疗法临床试验总结 5 联合治疗：目前CD40/CD40L靶向治疗临床效果有限，联合免疫刺激疗法可增强抗肿瘤反应。联合化疗可增加肿瘤抗原的可用性，联合ICI可增强肿瘤特异性T细胞的活性和功能，联合TLR激动剂可增强T细胞反应，还可与抗血管生成治疗等联合。在临床应用中，针对不同类型的肿瘤，如非炎症性肿瘤（如胰腺癌、结直肠癌）可联合化疗，炎症性肿瘤（如膀胱癌）可联合ICI，以提高治疗效果。 表7 CD40-CD40L 靶向治疗的临床疗效总结 5 仁域 CD40/CD40L与自身免疫性疾病 系统性红斑狼疮(SLE)：SLE患者的CD40/CD40L表达均上调，血清中sCD40L水平也增加。在SLE的发病过程中，CD40L在Tfh细胞上表达，驱动生发中心内B细胞的异常活化和分化，产生大量自身抗体，可促进免疫细胞间的相互作用，增强炎症反应，引发组织损伤，与疾病的进展密切相关。此外，CD40L还可与整合素家族受体结合，促进炎症因子释放，增强血小板活化和聚集，影响SLE的发病和进展。阻断CD40/CD40L通路可降低抗双链DNA抗体滴度，改善疾病相关指标。 图9 CD40/CD40L在SLE发病机制中相互作用的模型 类风湿关节炎(RA)：在RA患者中，CD40和CD40L的表达均上调，CD40L在T细胞上的过表达与疾病活动度相关，高水平表达往往伴随着更高的疾病活动和更少的缓解。CD40通路不仅参与了RA患者体内类风湿因子等自身抗体的产生，还直接影响滑膜成纤维细胞的功能。当滑膜成纤维细胞上的CD40与CD40L结合后，会促使细胞产生TNF、IL-1β和MMPs等炎症介质，进一步加剧炎症反应和关节破坏。 银屑病关节炎(PsA)：PsA患者的CD40L表达增加。CD40/CD40L信号通路的异常激活，促进了免疫细胞的活化和炎症细胞因子的分泌，如IL-17、IL-23等，参与皮肤和关节的炎症反应，导致皮肤病变和关节损伤。在皮肤病变中，CD40/CD40L信号通路可能通过影响角质形成细胞的增殖和分化、炎症细胞的浸润，并参与银屑病的发病过程。在关节部位，CD40/CD40L信号通路还可促进滑膜细胞的炎症反应和骨侵蚀。 强直性脊柱炎(AS)：在AS患者中，CD40/CD40L信号通路也参与了疾病的发生发展。CD40L在T细胞、单核细胞等免疫细胞上表达上调，与CD40结合后，激活下游信号通路，促进炎症细胞因子的分泌，可引起脊柱关节和骶髂关节的炎症反应，导致关节疼痛、僵硬和骨质破坏。此外，CD40/CD40L信号通路还可能影响成骨细胞和破骨细胞的功能，打破骨代谢平衡，导致新骨形成和骨赘形成，最终引起脊柱强直和关节畸形。 干燥综合征(Sjögren'ssyndrome)：CD40/CD40L相互作用会诱导细胞表达黏附分子如ICAM-1，促进炎症细胞的浸润和组织损伤。在小鼠模型中，阻断CD40/CD40L通路可预防干燥综合征的发生发展，表明该通路在疾病进程中起着重要作用。 自身免疫性肾炎(如FSGS)：在局灶节段性肾小球硬化(FSGS)中，正常情况下肾脏不表达CD40，但患者的肾小球足细胞会异常表达CD40，且可被CD40L进一步诱导。可能导致足细胞功能受损，如改变细胞的肌动蛋白细胞骨架，增加肾小球的通透性，进而引发蛋白尿和肾脏损伤。 炎症性肠病(IBD)：包括克罗恩病(CD)和溃疡性结肠炎(UC)。在IBD患者中，CD40L和CD40在循环系统和肠道黏膜中均高表达。CD40/CD40L相互作用可诱导肠道微血管内皮细胞产生趋化因子和细胞因子，促进炎症细胞浸润，破坏肠道屏障功能，与疾病的病理生理过程直接相关。 自身免疫性皮肤疾病(如系统性硬化症SSc和SLE皮肤病变)：在系统性硬化症中，皮肤成纤维细胞的CD40表达显著上调，与CD40L结合后，会促使成纤维细胞产生IL-6、IL-8等促炎细胞因子和趋化因子，还可诱导CD80表达，加剧炎症反应。同时，CD40L在血液T细胞和皮肤病变部位也高表达，sCD40L与疾病的血管并发症和自身抗体产生相关。在SLE皮肤病变中，也存在CD40/CD40L通路的异常激活。 1型糖尿病(T1D)：人类胰腺导管细胞和胰岛β细胞均表达CD40，与CD40L结合后会产生促炎细胞因子，可能参与T1D的发病过程以及胰岛移植后的排斥反应。T1D患者体内sCD40L水平和血小板表面CD40L表达均显著升高，为CD40的激活提供了更多来源。 多发性硬化症(MS)：MS患者血清中sCD40L水平与血脑屏障破坏的指标存在相关性，B细胞可通过CD40途径被激活，增强CD8+T细胞的颗粒酶B分泌。但也有研究表明MS患者血清中sCD40L水平降低，且CD40基因的一个等位基因及其mRNA表达降低与MS发病风险相关，说明该通路在MS中的作用较为复杂。 6 仁域 CD40/CD40L与神经系统疾病 创伤性脑损伤：CD40和CD40L在创伤部位的巨噬细胞和小胶质细胞上表达，血清sCD40L水平与TBI严重程度及30天死亡率正相关，降低CD40表达可减轻脑水肿。 阿尔茨海默病：CD40L刺激小胶质细胞干扰APP处理和tau磷酸化，导致神经纤维缠结和β-淀粉样斑块形成，其在淀粉样斑块周围的星形胶质细胞中有强烈免疫反应。 帕金森病：CD40刺激小胶质细胞和星形胶质细胞后，上调的诱导型一氧化氮合酶和环氧化酶-2可能导致多巴胺能神经元选择性丢失。 缺血性中风：CD40L在动脉粥样硬化相关细胞中表达，可降低斑块稳定性。在动物模型中，CD40和CD40L缺陷小鼠的梗死体积减小。 癫痫：在中风后癫痫患者中，血浆sCD40L水平和白细胞中CD40表达显著升高，下调CD40-CD40L可减轻动物模型的癫痫易感性和严重程度。 神经损伤：在脊髓损伤动物模型中，CD40+小胶质细胞增加，促进CD40L+T细胞浸润和细胞因子介导的损伤，还会通过多种机制导致神经性疼痛。 多发性硬化：患者的脱髓鞘斑块中，T细胞和小胶质细胞分别表达CD40L和CD40，相互作用后释放多种物质增加脱髓鞘，CD40表达的B细胞也参与其中，同时该信号与血脑屏障破坏有关。 肌萎缩侧索硬化：约56%患者血液中CD40信号上调，针对CD40L的单克隆抗体可延缓小鼠瘫痪并延长生存期。 重症肌无力：CD40L基因敲除小鼠对MG诱导完全抵抗，失调的CD40信号会破坏免疫耐受。 脑肿瘤：在胶质瘤中，CD40/CD40L的表达与预后相关，激动剂可增强肿瘤内T细胞反应，但也会导致肿瘤侵袭性、克隆性和耐药性增加，还会促进肿瘤血管生成。 图10 CD40/CD40L对神经病学的影响 7 仁域 CD40/CD40L与心血管疾病 动脉粥样硬化：CD40/CD40L广泛表达于动脉粥样硬化病变处的多种免疫和非免疫细胞上，促进炎症细胞因子分泌、细胞黏附分子表达以及细胞间的相互作用，影响脂质代谢和斑块稳定性；同时，CD40基因的单核苷酸多态性与动脉粥样硬化易感性相关，而可溶性CD40L对动脉粥样硬化的影响存在争议，整体上抑制CD40-CD40L系统虽可能预防动脉粥样硬化，但长期抑制会带来免疫抑制等问题。 图11 动脉粥样硬化中的CD40/CD40L相互作用 8 仁域 CD40/CD40L与恶性肿瘤 分析TCGA数据库发现，CD40在黑色素瘤、肾细胞癌和胰腺癌中均有表达，且与多种免疫相关基因存在相关性，这些基因涉及抗原呈递、T细胞功能等。 表8 CD40L对不同类型癌症的影响 抗体发现服务 & 产品 01 羊驼免疫&骆驼免疫—自建现代化养殖农场 02 万亿级天然抗体库产品—轻松DIY科研抗体 03 配套产品—助您轻松搭建基因工程抗体平台 关于仁域生物 成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。 可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！ protocol 获取 / 产品咨询 邮箱｜find@renyubio.com 电话｜19136178673 地址｜成都市经开区科技产业孵化园 关注我们，持续更新相关内容 参考文献 Fatima T, Mirza A, Fatima F, Karamat RI, Ahmad B, Naeem S, Shahid I, Akilimali A. 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