news
The FDA approval on December 3 of Amgen’s bispecific antibody Blincyto (blinatumomab) for treating a rare form of B-cell acute lymphoblastic leukemia is a notable milestone in the development of a technology that has been a long time coming. The Blincyto approval validates Amgen’s $1.16-billion acquisition of its developer, Micromet, in 2012 (Nat. Biotechnol. 30, 300–301, 2012). Its arrival on the market— combined with a recent burst of deal making as big pharma firms move on what they consider the most promising platforms and molecules— signals that bispecific antibody technology is now entering a phase of maturation. No other bispecific molecule is in late-stage trials, however, so it will take some time before the present momentum in the field feeds into multiple product approvals. The approval is not a world first. Almost six years ago, the European Medicines Agency approved another bispecific antibody, Removab (catumaxomab), for treating malignant ascites, a build-up of cancerous fluid in the peritoneal cavity (Table 1). That product from Trion Pharma, of Munich, was based on old technology, however, and it did not make a major commercial impact. Its high levels of immunogenicity, due to its chimeric origin, limited its use. Trion entered bankruptcy proceedings in 2013. As a concept, bispecific antibodies followed soon after their monoclonal antecedents. But it has taken some time to realize the concept on
an industrial scale. “The idea of putting two specificities in a single recombinant molecule has been around for 30 years,” says Scott Koenig, CEO of Macrogenics, of Rockville, Maryland. The challenge has been to maintain desired physicochemical and pharmacokinetic properties while achieving high levels of product homogeneity and yield. Initial efforts were hampered by drawbacks on several fronts, including lack of stability, aggregation leading to loss of solubility, a lack of homogeneity leading to purification problems and low manufacturing yields due to poor protein expression (mAbs 5, 962–973, 2013). Jan van de Winkel, CEO of Copenhagenbased Genmab, recalls from his time at sister firm Medarex (now part of Bristol-Myers Squibb, of New York) a bispecific technology based on the chemical conjugation of Fab fragments. “It worked in the lab, it worked in animals, but it didn’t work on a large scale,” he says. Since then, bispecific antibody developers have painstakingly worked out which specific local modifications can be introduced to achieve particular protein-engineering goals. Scientists at AbbVie in North Chicago, Illinois, recently reported that adjusting the length and composition of linker sequences that form part of its tetravalent, dual-variable-domain immunoglobulin (DVD-Ig) format influences the affinity of two of the molecule’s ‘inner’ variable domain regions (mAbs 5, 358–363, 2013). Genmab has
Bayne Stanley/Alamy
npg
© 2015 Nature America, Inc. All rights reserved.
Amgen’s bispecific antibody puffs across finish line
Amgen’s Neupogen, the first biosimilar for which has been given the FDA’s blessing.
nature biotechnology volume 33 NUMBER 3 MARCH 2015
219
NEWS Table 1 Selected bispecific antibodies in clinical trials Developers
Lead molecule
Targets
Technology
Indications
Clinical stage
Trion Pharma, Neovii Biotecha (Munich)
Removab
Epithelial cell adhesion molecule (EpCam) × CD3
Triomab quadroma technology comprising hybrid mouse IgG2a × rat IgG2b antibody with intact immune effector functions
Malignant ascites
EU approval Apr. 23, 2009
Amgen (Thousand Oaks, California)
Blincyto
CD19 × CD3
Bispecific T-cell engager (BiTE) antibodies Philadelphia chromosome– negative acute lymphoblastic comprising different minimal antigenbinding domains from two single-chain Fvs leukemia (scFvs) arranged in tandem on a polypeptide chain
Amgen
AMG-110
EpCam × CD3
BiTE antibody
Solid tumors
Phase 1
AbbVie
ABT-122
TNF-a x IL-17
DVD-Ig comprising tetravalent bispecific antibody with two additional variable domains, attached by linkers to the N-termini of the VH and VL domains of a conventional monoclonal antibody
Rheumatoid arthritis
Phase 2
AbbVie
ABT-981
© 2015 Nature America, Inc. All rights reserved.
Affimed Therapeutics AFM13
npg
FDA approval Dec. 3, 2014
IL-1a × IL-1b
DVD-Ig
Osteoarthritis
Phase 2
CD30 × CD16A
Tetravalent bispecific tandem diabody (TandAb) comprising four Fv domains joined by peptide linkers
Hodgkin lymphoma
Phase 2
Merrimack Pharmaceuticals (Cambridge, Massachusetts)
MM-111
Human epidermal growth factor receptor 2 (HER2) × HER3
Bispecific antibody fusion protein compris- Gastric cancer ing two scFv domains linked by modified human serum albumin
Phase 2
Sanofi (Paris)
SAR156597
IL-4 × IL-13
Tetravalent bispecific tandem immunoglobulin (TBTI)
Idiopathic pulmonary fibrosis
Phase 2
Roche (Basel)
RG7221 (RO5520985)
Bispecific IgG1 Crossmab antibody based Angiopoietin 2 (Ang-2) × vascular endothelial growth on knob-into-hole mutations and Fab domain exchange factor a (VEGF-A)
Colorectal cancer
Phase 2
Roche, Chugai (Tokyo) RG6013 (ACE910)
Factor IXa × factor X
Asymmetric bispecific IgG4 antibody
Hemophilia A
Phase 2
Genentech (S. San RG7597 Francisco, California) (MEDH7945A)
Epidermal growth factor receptor (EGFR) × HER3
Two-in-one IgG1 antibody
Phase 2 KRAS wild-type metastatic colorectal cancer; recurrent/ metastatic head + neck cancer
Ablynx (Ghent, Belgium), Merck Serono (Darmstadt, Germany)
ALX-0761
IL-17A × IL-17F
Bispecific nanobody with albumin-binding Autoimmune disease domain
Phase 2
Merus (Utrecht, the Netherlands)
MCLA-128
HER2 × HER3
Biclonics full-length bispecific antibody
Solid tumors
Phase 1/2
AstraZeneca (London), Amgen
MEDI-565 (AMG-211)
Carincoembryonic antigen × CD3
BiTE antibody
Gastrointestinal adenocarcinoma
Phase 1
Macrogenics, Servier (Suresnes, France)
MGD006
CD123 × CD3
Dual-affinity retargeting (DART) bispecific Acute myeloid leukemia antibody based on two covalently linked Fv polypeptides
Phase 1
CD20 × CD3
Bispecific antibody
Phase 1
Regeneron (Tarrytown, REGN1979 New York) aFormerly
Fresenius Biotech. Sources: company websites, PubMed
learned how to apply the Fab arm exchange process that occurs naturally with IgG4 antibodies to its Duobody bispecific IgG1 format, by matching point mutations at the interface between two CH3 domains from each parent IgG1 molecule. The reduction in vitro of hinge disulfide bridges drives the correct recombination of the two binding arms. Genmab’s manufacturing process achieves a purity of 95% at kilogram scale (mAbs 5, 962–973, 2013). For Affimed, of Heidelberg, Germany, the availability of a capture resin for protein purification was an important milestone in the development of its TandAb tandem antibody technology. The company initially grappled with manufacturing problems as well. “It has been an issue, but over time we have learned the relevant know-how,” says CEO Adi Hoess. 220
Advanced malignancies
Many companies persevered in the effort, spurred on both by the potential promise of bispecific antibodies and by the shortcomings of their monoclonal counterparts, very few of which are completely effective. Hitting one target on a signaling pathway, in cancer or autoimmune disease, for example, typically offers some patients—usually not all— short-term remission. The effect is often lost, because of the emergence of tumor resistance or the presence of redundant signaling pathways. By hitting two targets, bispecific antibodies offer a closer approximation of the body’s polyclonal antibody response than monoclonal antibodies can. Van de Winkel says “a handful” of antibodies, sometimes as little as two, tends to dominate a polyclonal response.
Bispecific antibody technology does not just offer a convenient way to pack a combination therapy into a single molecule. Many of the first bispecifics in clinical development for cancer, including Blincyto, combine an immune activation mechanism with a tumor-targeting mechanism. The CD3 component of the T-cell receptor complex is the most popular—targeting it, along with a tumor antigen, enables drug developers to unleash a T-cell response in a targeted fashion. Affimed claims a lead in directing the activity of natural killer (NK) cells in the same way. “Specific NK-cell engagement is very difficult to achieve, as most of the receptors on NK cells are also present on other cell types,” says Hoess. The company took over four years to develop a molecule that could distinguish between CD16A,
volume 33 NUMBER 3 MARCH 2015 nature biotechnology
a receptor expressed on NK cells, macrophages and mast cells, which triggers NK-cell-mediated killing of tumor cells, and CD16B, which is expressed on granulocytes and which does not trigger cell killing (mAbs 6, 727–738, 2014). “It’s technically extremely challenging because there are only a couple of amino acid differences between them,” he says. The appeal of bispecific antibodies has a commercial as well as a clinical dimension, given the wave of patent expirations about to break over many lucrative antibody franchises and ongoing progress in the development of a regulatory pathway for complex biosimilar products. For some firms, bispecific molecules are now center stage in their early-stage development. About 65% of Genmab’s preclinical programs— both in-house and partnered—are based on its Duobody bispecific technology, for example. “I believe this is going to be the single biggest driver of future income in the antibody space,” says van de Winkel. AbbVie is actively developing a bispecific successor to its rheumatoid arthritis drug Humira (adalimumab). Although now the world’s bestselling drug—sales topped $12.5 billion in 2014—the tumor necrosis factor alpha (TNFa) inhibitor is by no means a cure. About 40% of patients on long-term therapy attain a 50% reduction in their symptoms (ACR50), as measured by the American College of Rheumatology disease activity score. Just 20% attain ACR70. Several firms, moreover, are developing biosimilar versions. By adding an interleukin-17 (IL-17)inhibiting capability to an anti-TNF-a inhibitor, AbbVie hopes to develop a next-generation successor to Humira. Preclinical studies in cellular systems and animal models provide the rationale. The IL-17 inhibitors [used as single agents or on their own] in rheumatoid arthritis have not been very competitive,” says Lisa Olson, vice president of discovery at AbbVie. Johnson & Johnson, of New Brunswick, New Jersey, which has a multiproduct, bispecific alliance with Genmab, is also exploring, having acquired
Schlieren, Switzerland–based Covagen last year. The latter firm had begun early-stage trials of COVA-322, a bispecific based on Covagen’s Fynomer scaffold technology, which targets IL-17A and TNF-a. Bispecific antibodies are so far aimed mainly at the same indications in which monoclonal antibodies have been successful, particularly cancer and autoimmune disease. The technology development effort is, however, based on a wider assumption that in complex diseases bispecifics will have effects that go beyond what monoclonal antibodies are capable of. AbbVie’s sole clinical program in osteoarthritis involves a bispecific antibody, ABT-981, which targets the b- and a-isoforms of IL-1. “We’re one of the last companies doing clinical development in osteoarthritis,” Olson says. It’s been a challenging indication for drug firms, as the clinical development process is difficult, and the regulatory approval pathway is unclear. “It follows you may need to do combination therapy or unite the two, as we’ve done in the DVD, to get the clinical effect that can be recognized,” says Olson. “We feel the same way about lupus.” The field is still too immature to predict the likely winners—and losers—in the big push to make bispecific antibodies a mainstream therapeutic modality. Although the BiTE format is the first to win a US Food and Drug Administration (FDA) approval, the technology is far from optimized. The short half-life of BiTE molecules necessitates intravenous infusion, which could limit their utility. Macrogenics, Genmab, Vancouver, Canada–based Zymeworks and San Francisco–based Cytomx Therapeutics are among the firms that have made much of the recent running, in terms of winning multiple big pharma deals. If bispecifics deliver on their promise, the market will be big enough to accommodate multiple players. “There’s no single platform that’s necessarily going to take over everything,” Koenig says. “It’s a little too early to dogmatically say platform A is going to win out over all the others.” Cormac Sheridan
Smartphone HIV test. Sam Sia and colleagues at Columbia University in New York coupled microfluidics with consumer electronics to create a smartphone app that simultaneously detects HIV and syphilis. The dongle, attaches to a smartphone by the headphone jack to perform a triplexed miniature immunoassay: HIV antibody, treponemal-specific antibody for syphilis and nontreponemal antibody for active syphilis infection. The test requires a single prick of blood and uses less than 4% of the smartphone battery. Healthcare workers in Rwanda tested 96 women at a clinic for preventing mother-child transmission. Using the app, workers obtained results in 15 minutes, with 92–100% sensitivity and 79–100% specificity. It costs $34 to manufacture the dongle, and $1.44 to run the test.
Tassaneewan Laksanasopin/ Columbia University
npg
© 2015 Nature America, Inc. All rights reserved.
news
nature biotechnology volume 33 NUMBER 3 MARCH 2015
Myriad settles BRCA disputes and moves on In February, GeneDx of Gaithersburg, Maryland, and Myriad Genetics of Salt Lake City, Utah, settled their patent dispute over BRCA testing, the final chapter of Myriad’s losing battle to retain its dominance in breast cancer diagnosis. Five other companies similarly engaged in litigation over BRCA 1 and BRCA 2 testing— Ambry Genetics of Aliso Viejo, California; Gene by Gene of Houston; Quest Diagnostics of Madison, New Jersey; LabCorp of Burlington, North Carolina; and Invitae of San Francisco— had settled earlier this year. Myriad’s attempt to retain its dominance in BRCA testing seemed like a losing proposition since the US Supreme Court ruled in 2013 that natural gene sequences are unpatentable (Ambry vs. Myriad Genetics). However, the court left open the possibility of patenting engineered molecules (cDNAs or oligos), which Myriad attempted to exploit to stop its competitors from offering BRCA tests. But in December 2014, the US Court of Appeals for the Federal Circuit upheld an earlier ruling by the US District Court for Utah, denying Myriad’s request for an injunction against its competitors. District Court Judge Selby had found last March that the company’s primers and probes are not patentable because they have the same sequence as the natural gene. Once the appeal was denied, Myriad forged agreements with Ambry, Quest, LabCorp and Invitae (Gene by Gene and Myriad had settled earlier in 2014) and now GeneDx. Under the terms of the settlements, Myriad agrees not to pursue any further litigation over the patents mentioned in the suit, but will not be compensating anyone for legal costs incurred, (which some view as a small victory for Myriad). The company has been working on gene panels for various diseases and signaled its interest in protein diagnostics with a recent acquisition of Crescendo Bioscience.
“I don’t have any crow’s feet anymore, and I don’t have any wrinkle lines above my nose. Now I can say I’m not just the CEO, I’m a user.” Brenton Saunders, the 44 year old CEO of Parsippany, New Jersey–based generic drug company Actavis, which, in January, acquired Allergan, and along with it, the company’s blockbuster product, Botox. (Forbes, 9 February 2015) “I’m not against the use of those tools [multiple herbicide–resistant crops]. I’m against their poor use. I want as big a tool chest as possible—and having all of them be effective, using them in a wise way, is ultimately where we want to go.” Bruce Maxwell, an agroecologist at Montana State University in Bozeman, on two new crop approvals. In January, the USDA approved the use of Monsanto’s cotton resistant to three herbicides, and its soybean, resistant to two, worrying some environmentalists that their overuse will lead to resistance. (Wired, 2 February 2015)
221
The FDA approval on December 3 of Amgen’s bispecific antibody Blincyto (blinatumomab) for treating a rare form of B-cell acute lymphoblastic leukemia is a notable milestone in the development of a technology that has been a long time coming. The Blincyto approval validates Amgen’s $1.16-billion acquisition of its developer, Micromet, in 2012 (Nat. Biotechnol. 30, 300–301, 2012). Its arrival on the market— combined with a recent burst of deal making as big pharma firms move on what they consider the most promising platforms and molecules— signals that bispecific antibody technology is now entering a phase of maturation. No other bispecific molecule is in late-stage trials, however, so it will take some time before the present momentum in the field feeds into multiple product approvals. The approval is not a world first. Almost six years ago, the European Medicines Agency approved another bispecific antibody, Removab (catumaxomab), for treating malignant ascites, a build-up of cancerous fluid in the peritoneal cavity (Table 1). That product from Trion Pharma, of Munich, was based on old technology, however, and it did not make a major commercial impact. Its high levels of immunogenicity, due to its chimeric origin, limited its use. Trion entered bankruptcy proceedings in 2013. As a concept, bispecific antibodies followed soon after their monoclonal antecedents. But it has taken some time to realize the concept on
an industrial scale. “The idea of putting two specificities in a single recombinant molecule has been around for 30 years,” says Scott Koenig, CEO of Macrogenics, of Rockville, Maryland. The challenge has been to maintain desired physicochemical and pharmacokinetic properties while achieving high levels of product homogeneity and yield. Initial efforts were hampered by drawbacks on several fronts, including lack of stability, aggregation leading to loss of solubility, a lack of homogeneity leading to purification problems and low manufacturing yields due to poor protein expression (mAbs 5, 962–973, 2013). Jan van de Winkel, CEO of Copenhagenbased Genmab, recalls from his time at sister firm Medarex (now part of Bristol-Myers Squibb, of New York) a bispecific technology based on the chemical conjugation of Fab fragments. “It worked in the lab, it worked in animals, but it didn’t work on a large scale,” he says. Since then, bispecific antibody developers have painstakingly worked out which specific local modifications can be introduced to achieve particular protein-engineering goals. Scientists at AbbVie in North Chicago, Illinois, recently reported that adjusting the length and composition of linker sequences that form part of its tetravalent, dual-variable-domain immunoglobulin (DVD-Ig) format influences the affinity of two of the molecule’s ‘inner’ variable domain regions (mAbs 5, 358–363, 2013). Genmab has
Bayne Stanley/Alamy
npg
© 2015 Nature America, Inc. All rights reserved.
Amgen’s bispecific antibody puffs across finish line
Amgen’s Neupogen, the first biosimilar for which has been given the FDA’s blessing.
nature biotechnology volume 33 NUMBER 3 MARCH 2015
219
NEWS Table 1 Selected bispecific antibodies in clinical trials Developers
Lead molecule
Targets
Technology
Indications
Clinical stage
Trion Pharma, Neovii Biotecha (Munich)
Removab
Epithelial cell adhesion molecule (EpCam) × CD3
Triomab quadroma technology comprising hybrid mouse IgG2a × rat IgG2b antibody with intact immune effector functions
Malignant ascites
EU approval Apr. 23, 2009
Amgen (Thousand Oaks, California)
Blincyto
CD19 × CD3
Bispecific T-cell engager (BiTE) antibodies Philadelphia chromosome– negative acute lymphoblastic comprising different minimal antigenbinding domains from two single-chain Fvs leukemia (scFvs) arranged in tandem on a polypeptide chain
Amgen
AMG-110
EpCam × CD3
BiTE antibody
Solid tumors
Phase 1
AbbVie
ABT-122
TNF-a x IL-17
DVD-Ig comprising tetravalent bispecific antibody with two additional variable domains, attached by linkers to the N-termini of the VH and VL domains of a conventional monoclonal antibody
Rheumatoid arthritis
Phase 2
AbbVie
ABT-981
© 2015 Nature America, Inc. All rights reserved.
Affimed Therapeutics AFM13
npg
FDA approval Dec. 3, 2014
IL-1a × IL-1b
DVD-Ig
Osteoarthritis
Phase 2
CD30 × CD16A
Tetravalent bispecific tandem diabody (TandAb) comprising four Fv domains joined by peptide linkers
Hodgkin lymphoma
Phase 2
Merrimack Pharmaceuticals (Cambridge, Massachusetts)
MM-111
Human epidermal growth factor receptor 2 (HER2) × HER3
Bispecific antibody fusion protein compris- Gastric cancer ing two scFv domains linked by modified human serum albumin
Phase 2
Sanofi (Paris)
SAR156597
IL-4 × IL-13
Tetravalent bispecific tandem immunoglobulin (TBTI)
Idiopathic pulmonary fibrosis
Phase 2
Roche (Basel)
RG7221 (RO5520985)
Bispecific IgG1 Crossmab antibody based Angiopoietin 2 (Ang-2) × vascular endothelial growth on knob-into-hole mutations and Fab domain exchange factor a (VEGF-A)
Colorectal cancer
Phase 2
Roche, Chugai (Tokyo) RG6013 (ACE910)
Factor IXa × factor X
Asymmetric bispecific IgG4 antibody
Hemophilia A
Phase 2
Genentech (S. San RG7597 Francisco, California) (MEDH7945A)
Epidermal growth factor receptor (EGFR) × HER3
Two-in-one IgG1 antibody
Phase 2 KRAS wild-type metastatic colorectal cancer; recurrent/ metastatic head + neck cancer
Ablynx (Ghent, Belgium), Merck Serono (Darmstadt, Germany)
ALX-0761
IL-17A × IL-17F
Bispecific nanobody with albumin-binding Autoimmune disease domain
Phase 2
Merus (Utrecht, the Netherlands)
MCLA-128
HER2 × HER3
Biclonics full-length bispecific antibody
Solid tumors
Phase 1/2
AstraZeneca (London), Amgen
MEDI-565 (AMG-211)
Carincoembryonic antigen × CD3
BiTE antibody
Gastrointestinal adenocarcinoma
Phase 1
Macrogenics, Servier (Suresnes, France)
MGD006
CD123 × CD3
Dual-affinity retargeting (DART) bispecific Acute myeloid leukemia antibody based on two covalently linked Fv polypeptides
Phase 1
CD20 × CD3
Bispecific antibody
Phase 1
Regeneron (Tarrytown, REGN1979 New York) aFormerly
Fresenius Biotech. Sources: company websites, PubMed
learned how to apply the Fab arm exchange process that occurs naturally with IgG4 antibodies to its Duobody bispecific IgG1 format, by matching point mutations at the interface between two CH3 domains from each parent IgG1 molecule. The reduction in vitro of hinge disulfide bridges drives the correct recombination of the two binding arms. Genmab’s manufacturing process achieves a purity of 95% at kilogram scale (mAbs 5, 962–973, 2013). For Affimed, of Heidelberg, Germany, the availability of a capture resin for protein purification was an important milestone in the development of its TandAb tandem antibody technology. The company initially grappled with manufacturing problems as well. “It has been an issue, but over time we have learned the relevant know-how,” says CEO Adi Hoess. 220
Advanced malignancies
Many companies persevered in the effort, spurred on both by the potential promise of bispecific antibodies and by the shortcomings of their monoclonal counterparts, very few of which are completely effective. Hitting one target on a signaling pathway, in cancer or autoimmune disease, for example, typically offers some patients—usually not all— short-term remission. The effect is often lost, because of the emergence of tumor resistance or the presence of redundant signaling pathways. By hitting two targets, bispecific antibodies offer a closer approximation of the body’s polyclonal antibody response than monoclonal antibodies can. Van de Winkel says “a handful” of antibodies, sometimes as little as two, tends to dominate a polyclonal response.
Bispecific antibody technology does not just offer a convenient way to pack a combination therapy into a single molecule. Many of the first bispecifics in clinical development for cancer, including Blincyto, combine an immune activation mechanism with a tumor-targeting mechanism. The CD3 component of the T-cell receptor complex is the most popular—targeting it, along with a tumor antigen, enables drug developers to unleash a T-cell response in a targeted fashion. Affimed claims a lead in directing the activity of natural killer (NK) cells in the same way. “Specific NK-cell engagement is very difficult to achieve, as most of the receptors on NK cells are also present on other cell types,” says Hoess. The company took over four years to develop a molecule that could distinguish between CD16A,
volume 33 NUMBER 3 MARCH 2015 nature biotechnology
a receptor expressed on NK cells, macrophages and mast cells, which triggers NK-cell-mediated killing of tumor cells, and CD16B, which is expressed on granulocytes and which does not trigger cell killing (mAbs 6, 727–738, 2014). “It’s technically extremely challenging because there are only a couple of amino acid differences between them,” he says. The appeal of bispecific antibodies has a commercial as well as a clinical dimension, given the wave of patent expirations about to break over many lucrative antibody franchises and ongoing progress in the development of a regulatory pathway for complex biosimilar products. For some firms, bispecific molecules are now center stage in their early-stage development. About 65% of Genmab’s preclinical programs— both in-house and partnered—are based on its Duobody bispecific technology, for example. “I believe this is going to be the single biggest driver of future income in the antibody space,” says van de Winkel. AbbVie is actively developing a bispecific successor to its rheumatoid arthritis drug Humira (adalimumab). Although now the world’s bestselling drug—sales topped $12.5 billion in 2014—the tumor necrosis factor alpha (TNFa) inhibitor is by no means a cure. About 40% of patients on long-term therapy attain a 50% reduction in their symptoms (ACR50), as measured by the American College of Rheumatology disease activity score. Just 20% attain ACR70. Several firms, moreover, are developing biosimilar versions. By adding an interleukin-17 (IL-17)inhibiting capability to an anti-TNF-a inhibitor, AbbVie hopes to develop a next-generation successor to Humira. Preclinical studies in cellular systems and animal models provide the rationale. The IL-17 inhibitors [used as single agents or on their own] in rheumatoid arthritis have not been very competitive,” says Lisa Olson, vice president of discovery at AbbVie. Johnson & Johnson, of New Brunswick, New Jersey, which has a multiproduct, bispecific alliance with Genmab, is also exploring, having acquired
Schlieren, Switzerland–based Covagen last year. The latter firm had begun early-stage trials of COVA-322, a bispecific based on Covagen’s Fynomer scaffold technology, which targets IL-17A and TNF-a. Bispecific antibodies are so far aimed mainly at the same indications in which monoclonal antibodies have been successful, particularly cancer and autoimmune disease. The technology development effort is, however, based on a wider assumption that in complex diseases bispecifics will have effects that go beyond what monoclonal antibodies are capable of. AbbVie’s sole clinical program in osteoarthritis involves a bispecific antibody, ABT-981, which targets the b- and a-isoforms of IL-1. “We’re one of the last companies doing clinical development in osteoarthritis,” Olson says. It’s been a challenging indication for drug firms, as the clinical development process is difficult, and the regulatory approval pathway is unclear. “It follows you may need to do combination therapy or unite the two, as we’ve done in the DVD, to get the clinical effect that can be recognized,” says Olson. “We feel the same way about lupus.” The field is still too immature to predict the likely winners—and losers—in the big push to make bispecific antibodies a mainstream therapeutic modality. Although the BiTE format is the first to win a US Food and Drug Administration (FDA) approval, the technology is far from optimized. The short half-life of BiTE molecules necessitates intravenous infusion, which could limit their utility. Macrogenics, Genmab, Vancouver, Canada–based Zymeworks and San Francisco–based Cytomx Therapeutics are among the firms that have made much of the recent running, in terms of winning multiple big pharma deals. If bispecifics deliver on their promise, the market will be big enough to accommodate multiple players. “There’s no single platform that’s necessarily going to take over everything,” Koenig says. “It’s a little too early to dogmatically say platform A is going to win out over all the others.” Cormac Sheridan
Smartphone HIV test. Sam Sia and colleagues at Columbia University in New York coupled microfluidics with consumer electronics to create a smartphone app that simultaneously detects HIV and syphilis. The dongle, attaches to a smartphone by the headphone jack to perform a triplexed miniature immunoassay: HIV antibody, treponemal-specific antibody for syphilis and nontreponemal antibody for active syphilis infection. The test requires a single prick of blood and uses less than 4% of the smartphone battery. Healthcare workers in Rwanda tested 96 women at a clinic for preventing mother-child transmission. Using the app, workers obtained results in 15 minutes, with 92–100% sensitivity and 79–100% specificity. It costs $34 to manufacture the dongle, and $1.44 to run the test.
Tassaneewan Laksanasopin/ Columbia University
npg
© 2015 Nature America, Inc. All rights reserved.
news
nature biotechnology volume 33 NUMBER 3 MARCH 2015
Myriad settles BRCA disputes and moves on In February, GeneDx of Gaithersburg, Maryland, and Myriad Genetics of Salt Lake City, Utah, settled their patent dispute over BRCA testing, the final chapter of Myriad’s losing battle to retain its dominance in breast cancer diagnosis. Five other companies similarly engaged in litigation over BRCA 1 and BRCA 2 testing— Ambry Genetics of Aliso Viejo, California; Gene by Gene of Houston; Quest Diagnostics of Madison, New Jersey; LabCorp of Burlington, North Carolina; and Invitae of San Francisco— had settled earlier this year. Myriad’s attempt to retain its dominance in BRCA testing seemed like a losing proposition since the US Supreme Court ruled in 2013 that natural gene sequences are unpatentable (Ambry vs. Myriad Genetics). However, the court left open the possibility of patenting engineered molecules (cDNAs or oligos), which Myriad attempted to exploit to stop its competitors from offering BRCA tests. But in December 2014, the US Court of Appeals for the Federal Circuit upheld an earlier ruling by the US District Court for Utah, denying Myriad’s request for an injunction against its competitors. District Court Judge Selby had found last March that the company’s primers and probes are not patentable because they have the same sequence as the natural gene. Once the appeal was denied, Myriad forged agreements with Ambry, Quest, LabCorp and Invitae (Gene by Gene and Myriad had settled earlier in 2014) and now GeneDx. Under the terms of the settlements, Myriad agrees not to pursue any further litigation over the patents mentioned in the suit, but will not be compensating anyone for legal costs incurred, (which some view as a small victory for Myriad). The company has been working on gene panels for various diseases and signaled its interest in protein diagnostics with a recent acquisition of Crescendo Bioscience.
“I don’t have any crow’s feet anymore, and I don’t have any wrinkle lines above my nose. Now I can say I’m not just the CEO, I’m a user.” Brenton Saunders, the 44 year old CEO of Parsippany, New Jersey–based generic drug company Actavis, which, in January, acquired Allergan, and along with it, the company’s blockbuster product, Botox. (Forbes, 9 February 2015) “I’m not against the use of those tools [multiple herbicide–resistant crops]. I’m against their poor use. I want as big a tool chest as possible—and having all of them be effective, using them in a wise way, is ultimately where we want to go.” Bruce Maxwell, an agroecologist at Montana State University in Bozeman, on two new crop approvals. In January, the USDA approved the use of Monsanto’s cotton resistant to three herbicides, and its soybean, resistant to two, worrying some environmentalists that their overuse will lead to resistance. (Wired, 2 February 2015)
221
