In Oncology, Antibody-Drug Conjugates Are a Hot Ticket

The antibody-drug conjugate (ADC) class has seen substantial growth since the first FDA approval of an ADC, Pfizer’s Mylotarg (gemtuzumab ozogamicin), in 2000. Mylotarg, which was used to treat patients with acute myeloid leukemia, wound up dampening some of the high hopes for ADCs. Pfizer took it off the market in 2010 after evidence from confirmatory trials showed it was associated with early deaths. The FDA then approved Mylotarg at a lower dose in 2017.

But fast forward to 2024, and optimism about ADCs has returned. More than a dozen ADCs have been approved by the FDA, and their current market value is estimated at $9.7 billion. By some accounts, it will almost double by 2028.

Three elements

ADCs are oncology treatments that have been compared to guided missiles or drones because they target specific surface antigens on tumor cells, deliver a cytotoxic payload and largely spare surrounding healthy cells and tissues. A review of ADCs for lung cancer published last year in the American Society of Clinical Oncology (ASCO) Educational Book said the roots of the ADCs can be traced back to the early 20th century when Paul Ehrlich, a Nobel Prize-winning German medical scientist, envisioned “magic bullet” cancer treatments that would zero in on cancer cells but leave healthy cells unaffected.

ADCs consist of an antibody that targets proteins that are expressed in abundance on cancer cells. Some of the current targets are HER2, TROP2 and HER3. The cancer-seeking antibodies are humanized so as not to stir up an immunological response that might limit their effectiveness. The ASCO review says that the majority of ADCs use an immunoglobulin G1 antibody because of its longer half-life and properties.

A “linker” connects the antibody to the cytotoxic payload that kills the cancer cells. The linker is critical; it has to keep the ADC intact in the bloodstream. If the cytotoxic drug were to detach before the ADC finds the cancer, the prematurely released drug would likely lead to serious side effects. But the linker also needs to be engineered to release the cytotoxic drug once the antibody has found its target. Some linkers are “cleavable” — they are designed to degrade when they are exposed to intracellular factors such as acidity, glutathione reduction or lysosomal proteases, the ASCO review explains. Others are not specifically cleaved, Instead, the cytotoxic payload is released when whole ADC complex degrades.

The third element of the ADC is its cytotoxic payload, which is designed to be released inside cancer cells after the ADC has gotten inside and the linker releases it. Early versions of ADCs used conventional agents such as methotrexate. More recent versions use more potent agents, such as antimicrotubule agents and topoisomeraseI inhibitors.

One of the key characteristics of ADCs is the ratio of cytotoxic drugs to antibody, the ASCO says. The drug-antibody ratio (DAR) is the average number of payload moieties attached to each monoclonal antibody. The ADCs that have been approved by the FDA have DARs that range from two to eight, according to the ASCO review.

The development and marketing of ADCs have attracted the interest of several biopharmaceutical companies, as evidenced by the recent surge in licensing deals between major pharmaceutical companies and smaller biotech companies that specialize in antibody-based cancer treatments. In 2023, there were more than 70 deals involving ADCs, which included Pfizer’s $43 billion acquisition of Seagen, a biotech in suburban Seattle that specializes in ADCs. Renewed interest in ADC investment has been fueled in part by improvements in linker and payload technologies that help address challenges, such as the potential for off-target toxicity. Johnson & Johnson, Merck and AbbVie have been among the recent dealmakers acquiring robust ADC pipelines. In its “Global Trends in R&D 2024” report, IQVIA estimated that ADCs account for 9% of the oncology treatments currently in development.

The following are some up-and-coming ADCs inherited by these companies through agreements with biotech developers.

Patritumab deruxtecan, ifinatamab deruxtecan and raludotatug deruxtecan

Merck entered into a $22 billion agreement with Japanese biotech company Daiichi Sankyo to jointly develop and market three ADC candidates globally, except for in Japan, where Daiichi Sankyo retains market exclusivity. The new pipeline includes patritumab deruxtecan, ifinatamab deruxtecan and raludotatug deruxtecan. Each targets a different antigen, but all deliver the same payload.

Patritumab deruxtecan was granted breakthrough therapy designation in December 2021 for the treatment of epidermal growth factor receptor (EGFR)-mutated metastatic or locally advanced non-small cell lung cancer (NSCLC) in patients for whom treatment with a third-generation tyrosine kinase inhibitor and platinum-based chemotherapy was not effective.

Patritumab deruxtecan consists of a HER3-targeting monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable enzyme-cleavable linker. In the phase 2 HERTHENA-Lung01 trial, patritumab deruxtecan showed clinically significant efficacy and a tolerable safety profile when given once every three weeks to patients with advanced EGFR-mutated NSCLC previously treated with a tyrosine kinase inhibitor and platinum-based chemotherapy.

Based on these positive results, Merck said it planned to file for FDA approval in March 2024. The phase 3 HERTHENA-Lung02 trial is ongoing. Results from the phase 2 trial were simultaneously presented at the International Association for the Study of Lung Cancer’s 2023 World Conference on Lung Cancer meeting and published in the Journal of Clinical Oncology in September 2023.

Ifinatamab deruxtecan is being evaluated in the phase 2 Ideate-01 trial for the potential treatment of extensive-stage small cell lung cancer in previously treated patients. The antibody in ifinatamab deruxtecan targets B7-H3, a protein overexpressed in several types of cancer cells, including small cell lung cancer.

Raludotatug deruxtecan is currently being investigated in a phase 1 study for the potential treatment of patients with advanced ovarian cancer. Raludotatug deruxtecan contains a monoclonal antibody that targets CDH6, a protein overexpressed by many types of cancer cells, including ovarian tumors.

ARX517, ARX788
and ARX305

In January 2024, Johnson & Johnson announced an agreement to acquire San Diego-based Ambrx Biopharma, an ADC-focused biopharmaceutical company, in a $2 billion all-cash deal. Through the acquisition, Johnson & Johnson will obtain potential first-in-class ADC candidates targeting markers in prostate cancer, HER2-positive breast cancer and renal cell carcinoma.

Johnson & Johnson plans to focus on accelerating the phase 1/2 APEX-01 study evaluating the use of an investigational ADC called ARX517 in patients with metastatic castration-resistant prostate cancer (mCRPC). ARX517 contains a monoclonal antibody that targets prostate-specific membrane antigen, a protein present in all prostate cells but highly expressed in mCRPC tumors. The antibody is linked to AS269, an investigational microtubule inhibitor payload, by a stable, noncleavable linker.

Johnson & Johnson is expected to close the deal acquiring Ambrx in the next several months. Other ADCs in Ambrx’s pipeline include ARX788, which targets metastatic HER2-positive breast cancer, and ARX305, which targets renal cell carcinoma.

Pivekimab sunirine
and IMGN-151

In February 2024, AbbVie closed a $10.1 billion deal acquiring ImmunoGen, an ADC-focused biotechnology company headquartered in suburban Boston. With the agreement, AbbVie gained Elahere (mirvetuximab soravtansine), the only ADC approved by the FDA as a treatment for ovarian cancer. AbbVie also acquired two ADC candidates in ImmunoGen’s pipeline as a result of the deal, pivekimab sunirine and IMGN-151.

Pivekimab sunirine, an investigational CD123-targeting ADC, is in phase 2 studies for the treatment of a rare blood cancer, blastic plasmacytoid dendritic cell neoplasm, and of acute myeloid leukemia. In addition to the anti-CD123 monoclonal antibody, pivekimab sunirine contains a cleavable linker and a novel indolinobenzodiazepine pseudodimer payload.

IMGN-151 is being investigated in phase 1 studies for the treatment of patients with ovarian cancer with the potential to expand indications into other solid tumors. The next-generation ADC comprises a bivalent antibody targeting two separate sites on folic receptor alpha and is linked to a maytansinoid derivative payload by a cleavable peptide linker.