First Preventive Mab for Hereditary Angioedema

NEWS Concerns over the safety of afucosylated EGFR is widely expressed on normal cells, First preventive mAb for antibodies have been, for the most part, Janssen’s antibody “is built in such a way that hereditary angioedema theoretical. Companies have nonetheless it only binds at high affinity cells that have The US Food and Drug Administration has remained vigilant for signs of increased both EGFR and c-Met,” says Strohl. “And approved the first monoclonal antibody immunogenicity, altered antibody pharma- 90% of those kind of cells, or 80% at least, (mAb) to prevent hereditary angioedema (HEA) attacks. Dublin-based Shire was given cokinetics, and any interference with other are going to be cancer cells.” Similarly, Merus, the go-ahead in August to market Takhzyro antibody effector functions. So far, none of in Utrecht, the Netherlands, has two afu- (lanadelumab) as prophylactic treatment for these problems have surfaced. “You don’t cosylated anticancer bispecifics in the clinic. HEA types I and II in patients aged 12 years have any systematic defects that accompany “Because we are simultaneously approach- or older. HEA is a rare but life-threatening defucosylation,” says Benjamin. “But it’s ing two different epitopes on a tumor, this genetic disease caused by mutations in the important to recognize that the antibodies allows for a more selective targeting,” says C1 esterase inhibitor gene, which leads to an overactivation of the complement are more potent, and therefore their intrinsic Merus chief development officer Lex Bakker. system. This can trigger unpredictable bouts biology does need to be “Because of that we are of subcutaneous or submucosal swelling studied and can be dif- For all their potency, able to put on additional anywhere in the body, potentially leading to ferent than a fucosylated afucosylated antibodies effector mechanisms in blocked airways, and in the gut the attacks antibody.” the Fc tail.” can cause intense pain, vomiting and But their potency can’t turn a bad target Many strategies exist dehydration. Takhzyro is a human mAb against means that afucosylated into a good one. to engineer antibod- kallikrein, an enzyme that is elevated in the antibodies are mostly ies without fucose, disease and is known to interact with the used to deplete entire cell populations. That although two platforms dominate the com- complement system. The drug’s approval carries the risk of collateral damage to other mercial market. The Potelligent platform, was based on data from four clinical studies, cells. “The challenge here is always to really from Kyowa Kirin’s BioWa subsidiary, uses including a 26-week phase 3 trial in 125 find the right target,” says Kolbeck. “You a proprietary CHO (Chinese hamster ovary) patients. They experienced 87% fewer HEA attacks if injected every 2 weeks and 73% want something which is really, really spe- cell line genetically engineered to knock out fewer if injected every 4 weeks, compared cifically expressed on the cell type you are the gene for FUT8, a fucosyltransferase, criti- with placebo. targeting.” This may be why Genentech cal for the assembly of the final Fc fucose. The Takhzyro entered Shire’s portfolio of HEA never advanced its afucosylated version of other platform is GlymaxX technology from therapies when the company acquired Dyax Herceptin (trastuzumab), despite in vivo ProBioGen in Berlin. This method overex- of Burlington, Massachusetts, in 2016 (Nat. Biotechnol. 34, 7, 2016). Shire also owns a superiority over the original (Cancer Res. 70, presses the GDP-6-deoxy-n-lyxo-4-hexulose portfolio of drugs for treating or preventing 4481–4489, 2010): because the target Her-2 reductase (RMD) enzyme to short-circuit HEA attacks, including Firazyr (icatibant), protein is widely expressed on normal cells. the fucose biosynthetic pathway in antibody a bradykinin B2 receptor, and Kalbitor (The company declined to comment for this production cell lines. Companies that want (ecallantide), a kallikrein inhibitor. These story.) At least three marketed antibodies— to develop afucosylated antibodies generally drugs are self-administered subcutaneously, Orencia (abatacept), Soliris (eculizumab) license one or the other, or create their own as is Takhzyro. The latter requires fewer injections than the other approved drugs, and NPlate (romiplostim)—are engineered system if they’re able to bypass ProBioGen which are also more limited in their efficacy for the opposite effect, for reduced Fc effec- and BioWa intellectual property. and carry more health risks. (Kalbitor is not tor function, to increase their safety margin. For all their potency, afucosylated anti- approved in Europe owing to concerns about Afucosylation, says Strohl, must be used bodies can’t turn a bad target into a good anaphylactic events.) These drugs also include very judiciously. “It’s a niche modification,” one. “There have been a lot of failures,” says attenuated androgens, fibrinolytic agents, he says. Strohl. Genentech’s quilizumab, for example, and intravenous human or recombinant C1 esterase inhibitors—such as Shire’s own Bispecific antibodies may be one special failed a randomized phase 2 trial in asthma Cinryze, CSL Behring’s Berinert and Pharming case. Indeed, several afucosylated bispecific (Respir. Res. 17, 29, 2016) and was discon- Group’s Ruconest. antibodies in development target proteins tinued. And MedImmune’s Fasenra, though An oral alternative is also in development. that are widely expressed on normal cells it worked in asthma, recently failed to meet A once-daily selective inhibitor of kallikrein (Table 1), seemingly violating the specific- its primary endpoint in two phase 3 trials developed by BioCryst Pharmaceuticals is being tested in two phase 3 trials for HAE ity deemed essential for their therapeutic in chronic obstructive pulmonary disease. prevention and in a phase 2 trial for treating use. Strohl, while head of biologics research But such setbacks have not slowed the cur- acute HAE attacks. If approved, the small at Janssen BioTherapeutics, helped develop rent wave. “We follow the science,” says molecule BCX7353 could become the first a bispecific antibody lacking fucose that MedImmune’s Kolbeck. “We like what we oral—and easiest-to-use—therapy for both targets the epidermal growth factor recep- have seen so far.” HEA treatment and prevention. tor (EGFR) and c-Met for cancer. Although Ken Garber Ann Arbor, Michigan Joana Osorio “I read the [Health and Human Services] “If a doctor is being paid to market under the “We already tolerate pretty huge levels of announcement with a great deal of cover of professional or academic standing, it inequality and unfairness in this society that skepticism. My instinct is that this is looks like an abuse of entrusted power for private we have. And I think that to try to add to driven by politics, and is part of the overall gain.” Brown University’s Roy Poses, president of that [by editing genes], exacerbate that, just effort to stigmatize and eventually criminalize the Foundation for Integrity and Responsibility in seems wrong.” Marcy Darnovsky, of the Center abortion.” Biomedical law professor Alta Charo Medicine, responds to news that GSK is resuming for Genetics and Society, responds to the of the University of Wisconsin reacts to the payments to doctors, which it had stopped after idea that genetic treatments might become a announcement that HHS cancelled a contract for paying a $3 billion fine for illegal marketing and luxury item. (Healthcare Analytics News, fetal tissue. (BuzzFeed, 25 September 2018) kickbacks. (STAT, 10 October 2018) 20 July 2018) NATURE BIOTECHNOLOGY VOLUME 36 NUMBER 11 NOVEMBER 2018 1027.

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