Plasmin-cleavable anti-insoluble fibrin antibody-drug conjugate
Inventors
Matsumura, Yasuhiro • Manabe, Shino • FUCHIGAMI, Hirobumi
Assignees
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Publication Number
US-11311626-B2
Publication Date
2022-04-26
Expiration Date
Abstract
The present invention relates to an antibody-drug conjugate (ADC) and a composition containing the conjugate for use in treating cancer. According to the present invention, provided are an ADC of an antibody specific to insoluble fibrin and a drug in which a linker linking the antibody and the drug has a plasmin cleavage sequence, and a pharmaceutical composition containing the ADC for use in treating cancer.
Core Innovation
The invention relates to an antibody-drug conjugate (ADC) comprising an antibody that binds to fibrin with an affinity to insoluble fibrin higher than that to fibrinogen. The ADC targets insoluble fibrin using fibrin-specific antibodies and links a cytotoxic agent to the antibody through a linker that contains a plasmin cleavage site allowing cleavage by plasmin.
The ADC is configured so that plasmin cleavage occurs in the presence of plasmin, enabling release of the cytotoxic payload at sites of insoluble fibrin accumulation. The linker includes a plasmin-cleavable sequence, including Val-Leu-Lys (VLLK), to support plasmin-dependent release.
The invention includes embodiments with specific monoclonal antibodies defined by heavy chain and light chain variable regions including CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs. The antibodies bind insoluble fibrin more strongly than fibrinogen using binding assessments including ELISA and surface plasmon resonance (SPR).
Supporting findings include accumulation at tumor sites and anti-cancer activity dependent on a plasmin-cleavable linker versus a non-plasmin (cathepsin) linker control.
Claims Coverage
The partial content provides three independent claims. Across these claims, the main inventive focus is an ADC that binds insoluble fibrin with higher affinity than fibrinogen and uses a plasmin-cleavable linker, and specific fibrin-binding antibodies defined by heavy-chain and light-chain CDR sequence identifiers.
Antibody-drug conjugate with insoluble fibrin higher affinity and plasmin-cleavable linker
An antibody-drug conjugate (ADC) wherein the antibody binds to fibrin and has affinity to insoluble fibrin higher than that to fibrinogen, the drug is a cytotoxic agent, and the antibody and the drug are linked through a linker having a plasmin cleavage site that allows cleavage by plasmin.
Fibrin-binding antibody with CDRs SEQ ID NOs 1-3 and 5-7
An antibody that binds to fibrin, wherein the antibody has a heavy chain variable region with CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and a light chain variable region with CDR1 set forth in SEQ ID NO: 5, CDR2 set forth in SEQ ID NO: 6, and CDR3 set forth in SEQ ID NO: 7.
Fibrin-binding antibody with CDRs SEQ ID NOs 9-11 and 13-15
An antibody that binds to fibrin, wherein the antibody has a heavy chain variable region with CDR1 set forth in SEQ ID NO: 9, CDR2 set forth in SEQ ID NO: 10, and CDR3 set forth in SEQ ID NO: 11, and a light chain variable region with CDR1 set forth in SEQ ID NO: 13, CDR2 set forth in SEQ ID NO: 14, and CDR3 set forth in SEQ ID NO: 15.
Across the independent claims, the invention is centered on fibrin-binding antibodies defined by specific heavy- and light-chain CDR sequence identifiers and an ADC that uses those antibodies with higher affinity for insoluble fibrin than fibrinogen, together with a linker containing a plasmin cleavage site for plasmin-dependent cleavage.
Stated Advantages
Favorable binding selectivity, where the antibody has higher affinity to insoluble fibrin than to fibrinogen.
Plasmin-dependent release of the cytotoxic payload at insoluble fibrin accumulation sites.
In vivo efficacy described as improved survival and suppression of tumor growth.
Documented Applications
Anti-cancer use in models described as pancreatic cancer, including a spontaneous pancreatic cancer model and a subcutaneous model involving tumor growth suppression.
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