Are Next-Gen Antibody-Drug Conjugates a Path Forward for Non-Hodgkin Lymphoma and Myeloma?
The Leukemia & Lymphoma Society partnered with Sutro Biopharma to test the safety of the investigational CD74-targeting antibody-drug conjugate STRO-001 for 2 blood cancers.
The Leukemia & Lymphoma Society (LLS) and Sutro Biopharma have partnered for a phase 1 clinical study of the firm's first-in-class, CD74-targeting antibody-drug conjugates (ADC) STRO-001 against refractory and/or relapsed non-Hodgkin lymphoma and multiple myeloma. CD74 is highly expressed on the surface of malignant B cells. Were it to prove safe and effective, STRO-001 could represent a much-needed treatment for patients whose current options are limited.
ADCs use engineered antibodies to target cancer cell surface proteins for delivery of a chemotherapy warhead, maximizing doses delivered to tumors while sparing surrounding tissues. Each ADC molecule contains a monoclonal antibody, a cytotoxic payload, and a covalent linker attaching these units.1,2
Early ADC development was challenging, beset by imprecise antibody-drug conjugation, unreliable targeting, off-target effects, and disappointing outcomes during clinical testing.1,2
Gemtuzumab ozogamicin, a CD33-directed ADC, was approved for treating acute myeloid leukemia (AML) until 2010, when it was voluntarily taken off the market following clinical trial evidence of increased patient mortality and the determination that there was no benefit from treatment with the drug compared with conventional therapies. In 2017, the product returned to the market with a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population.
The CD30-targeting ADC brentuximab vedotin is a treatment for relapsed or refractory Hodgkin lymphoma, systemic anaplastic large cell lymphoma, relapsed primary cutaneous anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides. The CD22-targeting ADC inotuzumab ozogamicin is used in the management of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).
“First-generation ADCs are limited by the fact that they are structurally heterogeneous populations in which the position and number of conjugated linkers and warheads vary significantly,” noted Lee Greenberger, PhD, chief scientific officer at the LLS.
But Dr Greenberger believes next-generation ADCs like STRO-001 are more attractive candidate treatments because of technological advances that make site-specific conjugation techniques less heterogeneous.
“CD74 is a protein highly expressed in B-cell malignancies such as multiple myeloma and lymphoma,” Dr Greenberger said. “STRO-001 consists of a single predominant conjugated species with a drug-antibody ratio of 2.”
Sutro's cell-free XpressCF™ and XpressCF+™ conjugation platforms separate protein-generating cellular components into an extract that contains “all the necessary biochemical components for energy production, transcription and translation, and can be used to support cell-free biochemical protein synthesis by the addition of the specific DNA sequence for the desired protein,” Dr Greenberger explained.