Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

T-Cell Redirection with bsAbs: As Risky CAR-T Cell Therapy?

Some scientists have suggested that bi- and multispecific antibody (bsAb) technology “will provide the next generation of targeted biologics for cancer therapy.” This optimistic assessment was echoed in a 2016 InsightPharma report saying that progress in bsAb research and the regulatory success of two bispecific molecules has led to an “explosion” of T-cell redirecting bsAbs. But many of the same side effects that plague chimeric antigen receptor (CAR) T-cell antibody therapy may afflict these next-generation antibody therapeutics. Mostly, these relate directly to the same immune system-invoking mechanisms that make CAR T-cell therapy effective in intractable blood tumors.

CAR T-Cell Therapies—Results and Problems

T-cell recruitment for cancer treatment in which activated, tumor-specific, cytotoxic T cells are aimed at malignant cells has generated interest and had some therapeutic successes in the treatment of blood cancers. Scientists from Juno Therapeutics, a biotech company developing CAR T-cell therapies, reported at the 2014 American Society of Hematology (ASH) meeting that in an ongoing Phase I trial its CAR T-cell therapy JCAR015 had induced remissions in 24 of 27 adults with refractive acute lymphoblastic leukemia (ALL)—with six patients remaining disease free for more than a year.

ALL remains extremely difficult to treat, progressing rapidly when it becomes refractory with most patients dying within a few months. “This response rate is unprecedented for patients who had stopped responding to all other treatments,” commented Michel Sadelain, M.D., Ph.D., a founding director of Memorial Sloan Kettering’s Center for Cell Engineering and a co-founder of Juno.

CARs, genetically engineered receptors that redirect T cells to a chosen tumor antigen, usually consist of three domains: an extracellular antigen-binding domain, a transmembrane domain, and at least one intracellular signal transduction domain genetically inserted into T cells using viral vectors, DNA transposons, or RNA transfection. When CARs bind to a tumor antigen, the intracellular signaling domain is activated and the tumoricidal process by T cells is initiated.

But the complicated nature of CAR T-cell therapy may prove a limiting step in its adoption, as it is a personalized therapy involving autologous T-cell collection, in vitro stimulation, CAR gene transduction, in vitro expansion, infusion of CAR T-cells, and generally requiring an average of 7–11 days.

In a 2016 report, Cai Xuan, Ph.D., GlobalData’s analyst covering oncology and hematology, said T-cell therapies being developed by companies that include Novartis, Juno Therapeutics, and Kite Pharma may be potential breakthroughs in oncology treatments for blood cancers. However, the per-patient cost is so high that the therapies must “demonstrate curative ability” before they can be considered as “a frontline treatment.” 

Dr. Xuan predicts a potential cost of such treatments as ranging between $300,000 and $500,000 per patient, while existing treatment options, including stem cell transplantation, range between $100,000 to $200,000. Dr. Xuan further noted that CAR T-cell therapies tailor-made for the individual patient involve a “complicated and expensive” manufacturing process. At present, such treatments are performed only at comprehensive medical centers with sophisticated laboratories staffed with personnel well-trained in the cryotherapy techniques of autologous T-cell proliferation and T-cell gene modification.

Are Bispecific Antibodies the Answer?

bsAbs have offered pharma companies averse to developing autologous therapies an alternative approach that may achieve similar results in blood cancers. These modified antibodies engage two different targets simultaneously, thereby bringing T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger cancer cell death.

The FDA’s approval on December 3, 2014, of Amgen's bispecific antibody Blincyto® (blinatumomab) for treating a rare form of B-cell ALL validated, from a U.S. regulatory perspective, the clinical development of these molecules.  Blincyto, developed using BiTE® (bispecific T-cell engagers) technology, is a fusion protein made up of the variable regions of two single-chain, variable fragments (scFvs)—CD19, a biomarker for normal and neoplastic B cells, and CD3 (on T cells)—recombinantly linked by a nonimmunogenic five-amino-acid chain.

Blincyto binds to CD19 highly expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells, forming a “synapse” between the cells, according to the company’s website. Once the synapse is formed, Blincyto leads to upregulation of cell-adhesion molecules and the production of cytolytic proteins that destroy the tumor cells.

Amgen acquired the antibody through its $1.16-billion cash acquisition of Micromet. The deal provided Amgen with both a cancer immunotherapy based on the bispecific monoclonal antibody (mAb) fragment blinatumomab, targeting B-cell antigen CD19 and T-cell receptor (TCR) component CD3, and the underlying BiTE technology that produced it.

Until the Blincyto approval, only Fresenius Biotech/Trion Pharma’s bsAb Removab® had reached the market, the European Medicines Agency (EMA) having approved the molecule for treating malignant ascites in 2009. Trion Pharma developed the molecule as a trifunctional bsAb, a tumor-antigen and CD3ema-binding hybrid of murine immunoglobulin G2a (IgG2a) and rat IgG2. Removab targets the epithelial cell-adhesion molecule (EpCAM) antigen on tumor cells, recruits T-effector cells via binding to the CD3ε subunit of the T-cell receptor complex, and activates monocytes, macrophages, dendritic cells, and natural killer (NK) cells by Fcγ-receptor binding.

Nonetheless, the Antibody Society has noted that despite encouraging preclinical results and clinical testing, additional successful outcomes in the clinic “have not been forthcoming.” Of the 20 novel bsAbs that entered first-in-humans clinical studies in 2014–2015, the society notes, about half invoke a T-cell recruiting mechanism. None of these have advanced—hampered in particular by toxicity and lack of significant antitumor response.

Pharma Activity Continues in the bsAb Space

But deal-making in the bsAb space continues, as recent agreements confirm Pharma’s continuing interest in these molecules, many believing that bsAbs may evolve enough to replace mAbs as safer, more effective antibody-like treatments for cancer and other diseases. Some antibody producers have devoted the majority of their resources to developing them. These resources focus on improving their efficacy and safety profile.

About 65% of Genmab's preclinical programs—both in-house and partnered—are based on its Duobody® bsAb technology. “I believe this is going to be the single biggest driver of future income in the antibody space,” said Genmab CEO Jan van de Winkel, Ph.D., in a comment to the journal Nature.

The company has used its Duobody bsAb IgG format in a manufacturing process that it says achieves a 95% purity rate. Gilead, in August 2016, entered an agreement with Genmab that gives Gilead an exclusive license to use the Danish drug-maker’s bispecific platform to create a human immunodeficiency virus (HIV) therapeutic, plus an option to take up another exclusive license on the technology.

Back in the cancer space, MacroGenics, a clinical-stage biopharmaceutical company that discovers and develops mAb-based therapeutics for the treatment of cancer, autoimmune disorders, and infectious diseases, said that the FDA has granted orphan drug designation to its bsAb MGD006, a dual-affinity retargeting (DART) T-cell redirecting molecule that recognizes both CD123 and CD3, for the investigational treatment of acute myeloid leukemia (AML). CD123, the IL-3 receptor α-chain, has been reported to be overexpressed on cancer cells in a wide range of hematological malignancies, including AML and myelodysplastic syndrome (MDS).

MGD006 is currently being evaluated in the U.S. and Europe in a Phase I dose-escalation study designed to assess the safety and tolerability of the molecule in patients with relapsed/refractory AML or MDS.

As clinical development and commercialization of CAR T-cell therapies run into significant trouble, bsAbs will continue to draw investors. Last year, Juno Therapeutics voluntarily halted its Phase II clinical trial of its CAR T-cell product JCAR015 following the death of five adult patients with relapsed or refractory B-cell ALL from cerebral edema. Beyond cerebral edema, patients undergoing the treatment can also develop “cytokine release syndrome,” in which the T cells release the cytokines that lead to severe fevers, nausea, difficulty breathing, low blood pressure, and organ swelling.

But Michael Schmidt, Ph.D., a biotech analyst at Leerink Partners, maintains “It’s the biggest discovery in oncology in the last decade or two.” No matter what happens with CAR T-cell therapies, “the promise of immunotherapy is definitely intact.”

Despite the fact that bsAbs can produce a similar array of life-threatening side-effects as CAR T-cell therapies, Dr. van de Winkel said he believes bsAbs will drive 60% of the growth in the therapeutic antibody field in the coming years, and might provide a safer and more druggable “analog” to CAR T-cell technology.

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