Compositions and methods for reducing off-target toxicity of antibody drug conjugates
Inventors
Balthasar, Joseph P. • BORDEAU, Brandon M. • NGUYEN, Toan Duc • POLLI, Joseph Ryan
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Assignees
Research Foundation of the State University of New York
Member
Glycos Biomedical LtdWe are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
We are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
Publication Number
US-12624123-B2
Publication Date
2026-05-12
Expiration Date
Abstract
Provided are compositions and methods for reducing off-target toxicity of antibody-drug conjugates (ADCs). The compositions comprise an ADC, and an agent targeted to the drug (payload) that is delivered by or derived from the ADC. The ADC and the agent targeted to the payload may be delivered together or separately in the treatment of various conditions (such as tumors) by ADCs. Examples of agents targeted to payload include antibodies, fragments, or modifications thereof.
Core Innovation
The invention relates to compositions comprising an antigen binding antibody fragment and a pharmaceutical carrier. The antigen binding antibody fragment comprises one of a plurality of specified sequences, including SEQ ID NO:3, a heavy chain and a light chain comprising SEQ ID NO:4 and SEQ ID NO:5, or SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:69.
The invention further provides compositions in which the antigen binding antibody fragment is associated with an antibody drug conjugate having a payload that is a camptothecin derivative. The disclosed approach is directed to reducing off-target toxicity and non-target toxicity associated with ADC payloads by inhibiting toxicity originating from free or cleaved payload while not broadly impairing tumor efficacy.
Payload-binding agents specifically bind the free or cleaved payload portion. The payload-binding agents include anti-payload antibodies and fragments such as Fab, scFv, and sdAb, as well as peptides and other binding mimetics, and target specific payload classes including camptothecins such as SN38, topotecan, and exatecan, and ADC payloads such as camptothecin derivatives including derivatives of SN38, topotecan, and exatecan.
Claims Coverage
The provided independent claim covers a pharmaceutical composition where an antigen binding antibody fragment with one of several specified sequence options is combined with a pharmaceutical carrier. The claim set further narrows this composition by selecting particular SEQ ID NOs and, in at least one dependent refinement, by incorporating an ADC whose payload is a camptothecin derivative.
Pharmaceutical composition with specified antigen binding antibody fragment sequences
A composition comprising an antigen binding antibody fragment and a pharmaceutical carrier, wherein the antigen binding antibody fragment comprises SEQ ID NO:3, a heavy chain comprising SEQ ID NO:4 and a light chain comprising SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:69.
Specific heavy-chain and light-chain sequence combination
The antigen binding antibody fragment comprises a heavy chain comprising SEQ ID NO:4 and a light chain comprising SEQ ID NO:5.
ADC payload as a camptothecin derivative
The composition further includes an antibody drug conjugate whose drug component is a camptothecin derivative.
Claim coverage is centered on a pharmaceutical composition combining a carrier with an antigen binding antibody fragment defined by specified SEQ ID NOs, with refinements selecting particular sequence options and, in at least one dependent refinement, including an ADC having a camptothecin-derivative payload.
Stated Advantages
Reduces off-target toxicity of ADC payloads by inhibiting toxicity from free or cleaved payload without broadly impairing tumor efficacy.
Selectively neutralizes toxicity from unconjugated payload while not preventing intact ADC cytotoxicity, and in some cases increases ADC cytotoxicity.
Documented Applications
Reducing off-target toxicity and non-target toxicity associated with ADCs by administering an ADC together with payload-binding agents that bind free or cleaved payload portions.
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