Though conceptually understood for decades, antibody-drug conjugates (ADCs) haven’t begun to come into their own until recently, but oncology drug developers continue to wrestle with challenges, large among them the problem of antigen selection. Lately, companies including names such as Adagene Inc., Bioatla Inc. and Cytomx Therapeutics Inc., have taken particular interest in exploiting features of the cancer growth itself to add more oomph, with focus on special features of the tumor microenvironment (TME).
The basic idea for ADCs’ design took shape in the 1960s, but it wasn’t until 2011 that a product won approval from the FDA – one that stayed in place, anyway. In Augustof that year, Seattle Genetics Inc. won the go-ahead for Adcetris (brentuximab vedotin) for Hodgkin lymphoma systemic anaplastic large cell lymphoma. The label wasexpanded to include several other indications in 2017 and 2018.
ADC strivers breathed a sigh of relief with Adcetris’ regulatory success, given the problems with Mylotarg (gemtuzumab ozogamicin), a D33-directed product from Pfizer Inc. for acute myeloid leukemia (AML). Mylotarg trails a long history. First granted accelerated approval in May 2000 as a standalone treatment for older patients with CD33-positive AML who had experienced a relapse, Mylotarg was voluntarily withdrawn by Pfizer in 2010 after confirmatory research failed to verify clinical benefit and turned up safety concerns. The FDA’s September 2017 approval of Mylotarg called for a lower dose, a different schedule in combination with chemotherapy or on its own, and a new patient population. It’s labeled for newly diagnosed CD33-positive AML in adults and for pediatric patients ages 1 month and up, as well as for relapsed or refractory CD33 AML in adults and pediatrics 2 years and older.
ADCs have chalked whopper deals already this year. In early February, Mersana Therapeutics Inc. and Macrogenics Inc. separately signed contracts worth $1 billion-plus and $586 million, respectively. Mersana partnered with Johnson & Johnson’s Janssen Biotech, which forked over $40 million up front and pledged more than $1 billion in potential milestone payments. Macrogenics Inc. agreed to a tie-up with Amsterdam-based Synaffix BV to combine the former’s antibody and bispecific DART technology
with Synaffix’s linker-payload technology. Immunogen Inc. signed with Eli Lilly and Co. an ADC pact that could be worth $1.7 billion.
But ADC skepticism lingers among investors, as shown by Immunogen’s overall positive phase III news in ovarian cancer March 21, on which the stock (NASDAQ:IMGN) sunk more than 18%.
The past three years have seen seven ADC approvals in solid as well as hematological cancers. More are due, no doubt, as researchers figure out ways to leap the hurdles – among which a major one involves the aforementioned antigen selection, which Piper Sandler analysts dubbed “a rate-limiting step” in the space. Rolling out a 118-page report Feb. 15, they noted that “within solid tumors, antibody-based therapies [such as] ADCs have been limited to only a handful of tumor antigens (HER2, Nectin-4, TROP-2, etc.), as many potential targets do not provide a sufficient therapeutic window,” with toxicity arising because the ADC’s target antigen also manifests in healthy tissue. (This is what foiled Boehringer Ingelheim GmbH’s bivatuzumab mertansine, which targeted the CD44v6 antigen, and Bayer AG’s BAY-794620, which took aim at CA9.) “Improving the tumor selectivity of the targeting moiety and minimizing or eliminating binding in normal tissue is one area being explored that could greatly expand the utility of ADCs,” the report said.
Among the notable players zeroing in on the TME is Adagene, of San Diego and Suzhou, China, with an artificial intelligence discovery platform called the Dynamic Precision Antibody Library, powers with modalities that go by several names. Neobody is tooled to come up with antibodies that put unique epitopes in the crosshairs by new means. Powerbody and Safebody drugs are meant to exploit the TME. Along with partnerships, the firm has three wholly owned antibodies that have reached the phase Ib/II stage. ADG-126 is a Safebody targeting CTLA4. The other two fall under the Neobody aegis, taking aim at CTLA4 and CD37. Early this month, Adagene inked a research collaboration with Paris-based Sanofi SA, to find “masked” monoclonal and bispecific antibodies in a deal worth up to $2.5 billion plus royalties. Adagene will invent masked versions of Sanofi prospects, taking responsibility for early stage research activities using Safebody. Sanofi will do later-stage research and all clinical, product development and marketing activities.
Cytomx, of South San Francisco, uses its Probody technology to make Probody drug conjugates (PDCs), also a masking effort. The strategy adds a protease-cleavable linker peptide to the N-terminus of an antibody that can be cleaved by proteases overexpressed by tumor cells, which makes an inactivated prodrug while in circulation but one that turns on when in the TME. Two PDCs have reached clinical development. The lead program with CX-2009 targets CD166 and is undergoing phase II investigation for hormone receptor-positive breast cancer and triple-negative breast cancer. Cytomx’s other compound, CX-2029, has reached the dose-expansion stage in phase II trials testing the drug against squamous non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (HNSCC), esophageal/esophagogastric junction tumors and diffuse large B-cell lymphoma. Updates from both programs are expected this year.
San Diego-based Bioatla is advancing what it calls Conditionally Active Biologics (CABs) that take advantage of the differential pH of cancer cells. The firm has two firstin- class CAB ADCs in phase II development: BA-3011 (mecbotamab vedotin), which targets AXL and is being tested as a monotherapy and in combination with PD-1 drugs in soft-tissue and bone sarcoma, NSCLC and ovarian cancer; and BA-3021 (ozuriftamab vetodin), which targets ROR2 and is being tested as a monotherapy and in combination with PD-1 therapies in NSCLC, melanoma, HNSCC and ovarian cancer.
Especially high on Bioatla is H.C. Wainwright analyst Arthur He, who holds a “buy” rating on the stock with a $25 price target. “The platform is quite versatile, in that it could be used to generate any antibody-based biologic,” he wrote in a March 21 report. “Only about 11% of total cancer patients respond to checkpoint inhibitors, while systemic toxicities limit the therapeutic potential of CAR T therapies as well as ADCs,” he pointed out. The stock (NASDAQ:BCAB) has reached a 52-week high of $59.19 and a low of $4.22. CAB “has the potential to become a disruptive technology in antibody-based cancer therapy for solid tumors,” he said, estimating that Bioatla would generate risk-adjusted revenues of $534 million in 2031, growing from $6 million in 2024.
Findings continue to surface regarding the TME. Researchers at the University of Notre Dame recently published their discovery of a way tumor cells transfer geneticmaterial to other cells. They described in a March 1 article in Cell Reports how DNA “cargo” is moved around by way of extracellular microvesicles.