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Antibody-drug conjugates remain front and center of the biopharma world. Following Enhertu’s historic agnostic approval in HER2-positive solid tumors and TIVDAK winning full approval, the field has seen a surge in multi-billion-dollar acquisitions, commercialization deals, and licensing agreements. These developments have enabled the ADC community to make strides in bringing these therapies to earlier-line treatments and expand their use to wider patient populations.
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In our latest episode of the new Antibody ABCs video series, we define immunotherapies. Watch the playlist here.
This Week’s News?
Trends – Advancing Immunotherapy for Amyloidosis: New Antibody Treatments and Investments
Amyloidosis is a rare disease characterized by the abnormal accumulation of misfolded proteins called amyloids in various organs and tissues, leading to organ dysfunction. These protein deposits can affect the heart, kidneys, liver, nervous system, and other areas, causing symptoms such as fatigue, swelling, numbness, and organ failure. There are different types of amyloidosis, including AL (light chain) amyloidosis, which is linked to plasma cell disorders, and ATTR (transthyretin) amyloidosis, which can be hereditary or age-related. Diagnosis typically involves blood tests, tissue biopsies, and imaging, while treatment depends on the type and severity, ranging from supportive care and chemotherapy to novel gene-silencing therapies and organ transplantation.?
Last week, Paradox Immunotherapeutics secured a $10M investment from SymBiosis to advance antibody therapies for protein misfolding diseases. Their approach involves lead identification and validation platform capable of developing antibodies that selectively target misfolded proteins while leaving healthy proteins untouched. In particular, Paradox is focused on the development of treatment for immunoglobulin light chain amyloidosis (AL amyloidosis), a complication of multiple myeloma that can lead to heart, kidney and liver failure, as well as treatment for leukocyte chemotactic factor 2 amyloidosis (LECT2), a severely underdiagnosed cause of chronic kidney disease and failure.
Meanwhile, a recent paper describes light-chain (AL) amyloidosis as a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in organs such as the heart and kidneys, leading to multi-organ dysfunction. While treatment has historically mirrored that of multiple myeloma (MM), recent advancements in MM immunotherapy, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and CAR T-cell therapy, are gradually being adopted for AL amyloidosis. However, due to the frailty of many AL patients, immune-mediated toxicities such as cytokine release syndrome (CRS) and neurotoxicity present significant challenges. Despite these risks, immunotherapy holds promise in achieving rapid and deep hematologic responses, potentially improving survival outcomes. Expanding access to these therapies through global initiatives and optimizing treatment strategies remain key to addressing unmet needs in AL amyloidosis management.
Another recent paper discusses the advances in understanding and treating transthyretin amyloidosis (ATTR), a disease characterized by amyloid fibril formation from misfolded transthyretin (TTR) proteins. It focuses on two monoclonal antibodies currently in clinical trials, ALXN-2220 and Coramitug. Through analyzing cryo-EM structures of TTR fibrils, the study reveals that while ALXN-2220 targets a flexible loop on the TTR protein, Coramitug and RT24 bind more rigid epitopes, potentially making them more effective at preventing amyloid formation. By examining the structures of TTR in its native, misfolded, and fibril forms, they identified epitopes that are exposed in diseased states but hidden in the native protein. These insights could aid in developing therapeutic antibodies not only for ATTR but also for other systemic amyloid diseases caused by protein misfolding.?
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