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Publication Number
US-11807692-B2
Publication Date
2023-11-07
Expiration Date
Abstract
Provided herein are DLL3 binding proteins and DLL3 targeting multispecific proteins (e.g., DLL3 targeting trispecific protein) comprising a domain binding to CD3, a half-life extension domain, and a domain binding to DLL3 (such as a DLL3 binding protein as provided herein). Also provided are pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors and host cells for making such DLL3 binding proteins, DLL3 targeting trispecific proteins. Also disclosed are methods of using the disclosed DLL3 binding proteins, DLL3 targeting trispecific proteins in the prevention, and/or treatment diseases, conditions and disorders.
Core Innovation
The invention relates to DLL3-targeting trispecific protein binders for treating a cancer overexpressing a DLL3 protein in a subject in need thereof. The trispecific protein comprises a first domain (A) that specifically binds human CD3, a second domain (B) that specifically binds human serum albumin, and a third domain (C) that specifically binds DLL3. The DLL3-binding third domain is defined by CDR1, CDR2, and CDR3 amino acid sequences corresponding to specified SEQ ID references and by amino acid sequence identity thresholds to indicated SEQ ID numbers.
The trispecific protein preferentially binds membrane-bound DLL3 over soluble DLL3. In the covered embodiments, the third domain includes CDR1, CDR2, and CDR3 sequences selected from multiple SEQ ID alternatives and is at least 80% identical to specified reference sequences.
The document further provides a DLL3 single domain antibody for treating cancer overexpressing a DLL3 protein in a subject. An exemplary DLL3/anti-CD3/anti-HSA trispecific protein configuration is also described, including CAT/TAC arrangement and domain/linker formatting, together with sequence listings for recombinant antibody/protein constructs and DLL3 targeting domain variants.
Claims Coverage
The independent claims cover methods of treating cancer overexpressing DLL3 by administering defined DLL3-targeting constructs. The core inventive features are trispecific domain composition with CD3, human serum albumin, and DLL3 binding, DLL3-binding third-domain definitions by SEQ ID-based sequence identity and specified CDR1/2/3 sequences, and a DLL3 single domain antibody defined by specified CDR1/2/3 sequences; one claim further limits the cancer to listed tumor sites or cancer types.
DLL3-targeting trispecific protein with CD3, human serum albumin, and DLL3 binding domains
A method of treating a cancer overexpressing a DLL3 protein in a subject by administering an effective amount of a DLL3 targeting trispecific protein comprising a single chain variable fragment specifically binding to human CD3, a single domain antibody specifically binding to human serum albumin protein, and a single domain antibody specifically binding to DLL3.
DLL3-binding third domain defined by SEQ ID identity and specified CDR1/CDR2/CDR3 alternatives
The third domain (C) comprises an amino acid sequence at least 80% identical to specified SEQ ID numbers and comprises CDR1, CDR2, and CDR3 amino acid sequences defined by the listed SEQ ID numbers, with multiple alternative DLL3-binding CDR sets described.
DLL3 single domain antibody defined by specified CDR1/CDR2/CDR3 sequences
A method of treating a cancer overexpressing a DLL3 protein in a subject by administering an effective amount of a DLL3 single domain antibody comprising CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID No. 874, SEQ ID No. 1316, and SEQ ID No. 1758.
Cancer indication limited to listed organ tumors or specified cancer types
The cancer comprises a tumor of an adrenal gland, liver, kidney, bladder, breast, gastric, ovary, cervix, uterus, esophagus, colorectum, prostate, pancreas, lung, thyroid, skin, or a head and neck, or the cancer comprises a carcinoma, a sarcoma, or a glioblastoma.
The claims collectively cover DLL3-targeted treatment methods using trispecific proteins with human CD3 and human serum albumin binding domains plus a DLL3-binding domain defined by SEQ ID identity and specified CDR1/CDR2/CDR3 sequences, as well as treatment with a DLL3 single domain antibody defined by specified CDR sequences. One claim also narrows the treated cancer to listed tumor sites or cancer categories.
Stated Advantages
Preferential binding of membrane-bound DLL3 over soluble DLL3.
Tumor growth reduction for DLL3-expressing tumors in vivo.
Reported quantitative response ranges versus controls.
Extended elimination half-time compared with shorter-half-life bispecifics.
Improved tissue penetration compared with shorter-half-life bispecifics.
Crosslinking T cells via CD3 to kill DLL3+ tumor cells.
Documented Applications
Treating a cancer overexpressing a DLL3 protein in a subject by administering an effective amount of a DLL3 targeting trispecific protein.
Treating a cancer overexpressing a DLL3 protein in a subject by administering an effective amount of a DLL3 single domain antibody with specified CDR1/2/3 sequences.
Using the trispecific protein for cancers including solid tumors and metastatic disease.
Using the trispecific protein for cancers of specified organ sites or specified cancer categories.
Administering the trispecific protein together with one or more specified co-therapies, including an anti-cancer agent and supportive or anti-side-effect agent classes.
Treating cancers comprising solid tumors, including specified organ sites and cancer types such as carcinoma, sarcoma, and glioblastoma.
Treating metastatic cancer overexpressing DLL3.
Preventing or treating proliferative or tumorous diseases including solid tumors and metastatic disease by targeting DLL3+ tumor cells via CD3-mediated T cell crosslinking.
Using DLL3-targeting trispecific proteins in immunotherapy constructs, including CAR designs with CD3 signaling components and DLL3 targeting.
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