Next-gen bispecific antibodies (BsAbs) are on the move. The blockbuster potential of the class has galvanized biopharma, with deals and assets racing to capture the pole position as the entire field gains speed.

These are not your father's Oldsmobile. While Blincyto (blinatumomab, Amgen Inc.) and Hemlibra (emicizumab-kxwh, Roche Holding AG/Genentech) helped to pave the road as the first generation of BsAb entrants, new classes and distinctive targeting combinations are looking to do to the early models what the infamous General Motors ad campaign did to one of its legacy brands. (See BioWorld Today, Dec. 4, 2014, and Nov. 17, 2017.)

Nearly 50 commercial candidates have entered the clinic, including a dozen in phase II and nearly three times that number in phase I, as indicated in the chart below. More than 140 additional BsAb assets remain in discovery, according to Cortellis Competitive Intelligence.

In their deep dive into the BsAb field, the research team at Piper Jaffray named more than three dozen public companies, from Amgen, Roche and their big biopharma brethren to mid-cap entrants such as Cytomx Therapeutics Inc. and Zymeworks Inc., as important players. By Piper's count, more than a dozen private companies also are active in the BsAb game. The 20 companies with the greatest number of disclosed BsAb assets in the space, according to Cortellis, are ranked in the chart below.

Piper generally defined development of bispecifics as dividing into five classes: bispecific immunoglobulin Gs (IgG) – the most common, with many of the advantages of natural antibodies; appended IgGs – the least common clinical format; BsAb fragments, the class from which Blincyto was the first to emerge; bispecific fusion proteins, or the fusion of antibody fragments; and alternative binding proteins, or small non-antibody domain scaffolds.

"We are bullish on the bispecific space and recommend a basket approach to playing this rapidly maturing platform," the Piper analysts wrote.

Big pharma placing multiple bets

It's hard to argue their point. In recent months, deals in the BsAb space have generated big headlines. In July 2018, Immatics Biotechnologies GmbH pocketed $54 million and the Tuebingen, Germany-based company stands to earn up to $1.65 billion more in development, regulatory and commercial milestones from a three-product immuno-oncology (I-O) research collaboration and license agreement with Genmab A/S, of Copenhagen, which is a leader in the BsAb arena. The companies will pool their respective capabilities in cancer target discovery, T-cell receptor engineering and antibody engineering to develop bispecific protein-based therapeutics targeting both intracellular tumor-associated peptides (Tumaps) and T cells. (See BioWorld, July 13, 2018.)

A month later, Affimed NV – working in the BsAb fragment class – allied with Roche unit Genentech to develop bispecific drugs that direct a natural killer (NK) cell response against multiple solid and hematological tumors. Affimed, of Heidelberg, Germany, pocketed $96 million in up-front and guaranteed near-term funding and could earn as much as $5 billion from development, regulatory and commercial milestones. (See BioWorld, Aug. 29, 2018.)

In addition to its adoptive NK cell transfer strategy, "Affimed is pursuing [B-cell maturation antigen] BCMA targeting and it is considered a potentially more selective target relative to CD123, which is associated with significant off-target effects," the Piper analysts wrote. "In addition, Affimed is pursuing co-targeting [of multiple myeloma cells] and dual targeting (of double positive myeloma cells) with their trispecific antibody. This offers both the potential for broader efficacy and increased selectivity."

Genentech parent Roche is hedging its bets. Among its BsAb entrants are RG-7828, an anti-CD3/CD20 bispecific IgG; RG-7221 (vanucizumab), an angiopoietin ligand-2/VEGF-A ligand inhibitor; and, with its Chugai Pharmaceutical Co. Ltd. subsidiary, RG-7802, a CD3/CD66e modulator, and mosunetuzumab, a B-lymphocyte antigen CD20/CD3 modulator.

In November, Beigene Ltd. became the latest in a string of collaborators with Zymeworks through a pair of BsAb deals that could potentially gross more than $1 billion for the Vancouver, British Columbia-based firm. (See BioWorld, Nov. 28, 2018.)

Suitors in other recent Zymeworks deals included Leo Pharma A/S, Merck & Co. Inc., Glaxosmithkline plc, Janssen Biotech Inc., Daiichi Sankyo Co. Ltd., Eli Lilly and Co. and Celgene Corp., positioning the company to accrue more than $7 billion in potential milestone payments. (See BioWorld, Nov. 14, 2017, May 16, 2018, and Oct. 24, 2018.)

Earlier this year, Abpro Therapeutics Inc. and NJCTTQ, a subsidiary of Nanjing Chia Tai Tianqing Pharmaceutical Group Co. Ltd., inked a U.S.-China BsAb cancer drug discovery deal that could bring Woburn, Mass.-based Abpro up to $4 billion in milestone fees and royalties, including $60 million in near-term R&D funding. Moreover, Abpro retained commercial rights outside China and Thailand for approved molecules. (See BioWorld, March 1, 2019.)

Early stage antibody developer Biomunex Pharmaceuticals SAS, of Paris, also lassoed a license agreement with neighboring big pharma Sanofi SA to develop bi- and multispecific antibodies based on its Bixab platform. Financial terms of that deal were not disclosed. (See BioWorld, Jan. 15, 2019.)

Sanofi has numerous BsAb stakes, in no small part through ownership of the nanobody fragment antibody platform gained through its $4.8 billion acquisition of Ablynx NV. The company is advancing SAR-156597, an IL-13/IL-4 receptor antagonist, in scleroderma. Sanofi and long-time partner Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., also are developing REGN-5458, an anti-BCMA/anti-CD3 BsAb, and REGN-4018, a CD3/mucin 16 modulator. (See BioWorld, Jan. 30, 2018.)

'You cannot rush to form a company'

Not all of the headlines in the BsAb space have been so flattering, especially on the clinical side. Last year, Merrimack Pharmaceuticals Inc., of Cambridge, Mass., said it would halt development of MM-141 (istiratumab) after top-line data from the phase II CARRIE study in front-line metastatic pancreatic cancer showed that adding the bispecific, tetravalent MAb to standard-of-care (SOC) nab-paclitaxel/gemcitabine failed to beat the SOC regimen plus placebo in the primary efficacy endpoint of progression-free survival (PFS). The study also missed secondary efficacy endpoints: objective response rate, disease control rate, duration of response and overall survival. (See BioWorld, June 26, 2018.)

In December, the FDA issued a partial clinical hold on a phase I test of the BsAb candidate MGD-009 (orlotamab), a B7-H3/CD3 bispecific Dual-Affinity Re-Targeting (DART) molecule from Macrogenics Inc., after high transaminase levels were seen in some participants. The hold, which did not affect participants already enrolled in the study, was lifted in January. (See BioWorld, Dec. 11, 2018.)

Other DART candidates from the Rockville, Md.-based company that have entered the clinic include flotetuzumab (CD123/CD3) and MGD-013, a CD223 antagonist/PD-1 inhibitor partnered with Zai Lab Ltd., of Shanghai.

Clinical setbacks serve as a reminder that companies active in the BsAb space need to walk before they can run, according to Jogender Tushir-Singh, who cautioned that testing core biology in specific models is the key to surviving what he termed an unfortunate "rat race" to success.

"Just because a PD-L1 showed promising results in [triple-negative breast cancer] patients doesn't justify making the decision to start a company that will pursue that approach in prostate or other cancers," Tushir-Singh told BioWorld Insight. "Cancer is a group of diseases. There are multiple things going wrong."

Increasing the immune response to attack cancer may result in unanticipated consequences, such as triggering or exacerbating heart disease, he pointed out.

"You cannot rush to form a company just because there are exciting data in a specific assay," Tushir-Singh said, pointing to the need for robust safety data compiled from multiple in vitro and in vivo models, up to and including non-human primates.

Bispecifics 'could be much more effective' than combos

Tushir-Singh, a veteran of Abbvie Inc. and Boehringer Ingelheim GmbH, is assistant professor in the University of Virginia's Department of Biochemistry and Molecular Genetics, where his team combined aspects of two antibodies that failed in earlier trials to create a BsAb that was able to shrink ovarian tumors in vivo. That antibody, dubbed a bispecific-anchored cytotoxicity activator, or BaCa, is now in the hands of the university's licensing office as work progresses on an IND filing, Tushir-Singh said. In the meantime, his team is working to apply the principles behind the BaCa antibody to other targets. (See BioWorld, Aug. 17, 2018.)

Tushir-Singh cited the findings on certain combination studies as a rationale to create bispecifics that could be even more powerful and effective. He referenced a paper by Hussein Tawbi, associate professor and director of melanoma clinical research and early drug development at the University of Texas M.D. Anderson Cancer Center, and academic and industry collaborators that showed a high response rate to the combination of nivolumab (Opdivo, Bristol-Myers Squibb Co.) and ipilimumab (Yervoy, BMS) to treat melanoma that metastasized to the brain. Findings, published last August in The New England Journal of Medicine, showed that, among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57 percent (95 percent confidence interval [CI], 47 to 68). The rate of complete response was 26 percent, partial response was 30 percent and stable disease for at least six months was 2 percent. The researchers determined the rate of extracranial clinical benefit was 56 percent (95 percent CI, 46 to 67).

Tushir-Singh called the clinical results "remarkable" in comparison to historic results with a single antibody.

"If you could reengineer those two antibodies into a bispecific antibody and try them in a clinical trial, it could be much more effective than injecting two different antibodies at two different doses," he suggested. The bispecific route likely would increase signaling ability and the propensity to engage both targets over co-administration of single molecules, which are more inclined to go their separate ways in the body, engaging different cells and reducing their overall effectiveness.

"This is really cool data," Tushir-Singh said. "We are working to make bispecifics even more effective than combining these single agent molecules."

Early findings from Impassion130, the phase III program evaluating the combination of atezolizumab (Tecentriq, Roche) and nab-paclitaxel (Abraxane, Celgene Corp.) in metastatic triple-negative breast cancer, also published last year in the New England Journal, offered similar motivation, he said, maintaining that a bispecific approach likely would improve the median PFS finding of 7.2 months in the combo arm compared with 5.5 months for placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95 percent CI, 0.69 to 0.92; p=0.002).

BsAb space bursting with partnerships

Biopharmas continue to see opportunities to move into new applications of BsAb technology and to get the science right.

Earlier this month, Agenus Inc., of Lexington, Mass., said it was due to receive a $7.5 million milestone payment from Foster City, Calif.-based Gilead Sciences Inc. for FDA acceptance of an IND for AGEN-1423, a BsAb designed to enhance the antitumor activity of myeloid cells, NK cells, T cells and cancer-associated fibroblasts.

Teneobio Inc., of Menlo Park, Ca., is producing a class of biologics it calls human heavy chain antibodies, or UniAbs, and producing the high-affinity BsAbs, specific for human CD3 and various tumor antigens, as T-cell engaging anti-cancer therapeutics. Though still preclinical, the company has a handful of assets, including bispecifics for multiple myeloma and HIV and in combination with immune checkpoint inhibitors.

Following the SVB Leerink Global Healthcare Conference last month, analyst Jonathan Chang called Xencor Inc.'s bispecific platform "an important long-term value driver for the company and a potential source of business development opportunities in the future."

Xencor, which has partnerships with Morphosys AG, CSL Ltd., Boehringer, Novartis AG and Amgen, is expecting phase I data this year from its fully owned CD3 bispecific programs that include XmAb-13676 (CD20/CD3) in B-cell malignancies and XmAb-18087 (somatostatin receptor 2/CD3) in neuroendocrine and gastrointestinal stromal tumors as well as initial data from its tumor microenvironment bispecific platform and initiation of phase I studies for XmAb-23104 (PD-1/ICOS) and XmAb-22841 (CTLA-4/LAG-3).

A preclinical data presentation on checkpoint-targeted IL-15/IL-15R-alpha-Fc fusions is expected next month at the American Association for Cancer Research annual meeting in Atlanta. In February, Xencor, of Monrovia, Calif., inked an IL-15 agreement with Genentech for $120 million up front, $160 million in development milestones for its XmAb-24306 program and up to $180 million in development milestones for each IL-15 drug candidate.

Other notable tie-ups in the space include Eli Lilly and China's Innovent Biologics Inc., which has yielded the hepatocyte growth factor receptor (HGFR) antagonist emibetuzumab. Epimab Biotherapeutics Inc., of Suzhou, China, is partnered with Wuxi Biologics Inc., of Shanghai, on EMB-01, an EGFR family tyrosine kinase receptor inhibitor/HGFR antagonist.

Merus NV and Incyte Corp. have a global collaboration and license agreement focused on the discovery and development of BsAbs that use Merus' Biclonics technology platform; MCLA-145, a CDw137 agonist/PD-L1 inhibitor, is the first asset to emerge from that partnership. Merck KGaA, meanwhile, has pacts with F-Star Delta, a subsidiary of F-Star Ltd., to develop and commercialize five bispecific I-O antibodies and with Glaxosmithkline plc to develop bintrafusp alfa, a PD-L1 inhibitor/TGF-beta type II receptor antagonist that's under evaluation in multiple solid tumors.

And there's Amgen, which also is paired with Cytomx in a potential $1.47 billion deal, including $40 million up front, to access as many as four T-cell engaging BsAbs and with Immatics to develop two bispecific T-cells engager molecules that target intracellular Tumap antigens.

'The window is very tight for T cell engagers'

Another BsAb prospect emerged this month at the 2019 World Immunotherapy Congress in San Diego when OSE Immunotherapeutics SA, of Nantes, France, revealed a platform dubbed Bicki that combines checkpoint inhibition with Treg inactivation. The technology is based on an engineered anti-PD-1 bifunctional antibody platform that can modify the tumor microenvironment by delivering costimulatory signals that increase anti-tumor T cell activities while also reinstating macrophage responsiveness to tumor tissue.

Nicolas Poirier, chief scientific officer, told BioWorld Insight the third-generation bispecific fusion protein platform was built on the company's backbone component anti-PD-1, OSE-279, while targeting innovative targets to increase antitumor efficacy by addressing untapped immune evasion mechanisms.

"Checkpoint inhibitors have clearly emerged as the new standard of care in oncology," Poirier said. Consequently, "many, many big pharma companies are now developing the big combinations of all of the immunotherapies that they have in their pipelines with PD-1 or PD-L1, but without a clear clinical or scientific rationale."

Echoing Tushir-Singh, Poirier agreed that combinations offer greater efficacy than monotherapy but that "one plus one usually equals 1.5 rather than two. What we found with our bispecific is that one plus one equals three, because the synergy between the two components exceeds that of the combination. The idea is that we have a very different bispecific platform where we are now combining immunotherapies and delivering them directly to the T cells that express PD-1," Poirier said, but in a selective manner. "The window is very tight for T cell engagers. We have a different window of opportunity."

Last year, OSE licensed preclinical I-O candidate, OSE-172, a SIRP-alpha antibody, to Boehringer Ingelheim for €15 million (US$18.5 million) up front, the potential for €15 million for initiation of a phase I study and more than €1.1 billion in development, commercialization and sales milestones, plus royalties on global net sales. That deal provided insight into OSE's BsAb approach. SIRP-alpha expressed on immune cells binds to CD47 on tumor cells, down-regulating myeloid lineage cells such as dendritic cells, tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs). By blocking SIRP-alpha, OSE-172 promotes the activation of T cells by turning MDSCs into effector cells, enhancing antigen presentation by dendritic cells and promoting phagocytic and inflammatory properties of macrophages in the tumor microenvironment. (See BioWorld, April 5, 2018.)

Earlier this month, OSE said it received regulatory approval to initiate the phase I study of the asset, now BI-765063, in France and Belgium.

'You could have a mess' by ignoring fundamentals

Although the academic world is far different from the field of commercial drug development, the talents of both are needed to move BsAb hopefuls across the finish line, especially in indications beyond cancer, according to Tushir-Singh. Although BsAb research has been driven by the bigger dollars behind oncology drug development, "there's a lot of potential for bispecific antibodies in inflammatory disease and even in heart disease," he suggested.

No matter the indication, studies in the space should be directed by the population and defined by established biomarkers, he insisted.

"Bispecific antibodies are highly selective," Tushir-Singh said. "If we can understand the biology, we can control them nicely to mitigate cytokine storms or other problems with safety and apply them to any disease."

Research teams that take the time to conduct "deep biology" will prevail in these efforts, he predicted.

"You have to walk and you have to see the ground," Tushir-Singh said. "If it's raining, you want to make sure you wear the right shoes. You can't wear flip flops because yesterday was a sunny day and somebody did a clinical trial on a sunny day. If it's raining, you could have a mess unless you're paying attention to the ground work: biology, safety, half life and many other fundamentals."