Anti-CD276 antibodies (B7H3)
Inventors
Dimitrov, Dimiter S. • Zhu, Zhongyu • St. Croix, Bradley • Seaman, Steven • Saha, Saurabh • Zhang, Xiaoyan Michelle • DeCrescenzo, Gary A. • WELSCH, Dean
Assignees
Biomed Valley Discoveries Inc • US Department of Health and Human Services
Publication Number
US-11851498-B2
Publication Date
2023-12-26
Expiration Date
2035-09-16
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Abstract
Polypeptides and proteins that specifically bind to and immunologically recognize CD276 are disclosed. Chimeric antigen receptors (CARs), anti-CD276 binding moieties, nucleic acids, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and conjugates relating to the polypeptides and proteins are also disclosed. Methods of detecting the presence of (a) cancer or (b) tumor vasculature in a mammal and methods of (a) treating or preventing cancer or (b) reducing tumor vasculature in a mammal are also disclosed.
Core Innovation
The invention provides polypeptides and proteins comprising antigen binding domains of anti-CD276 antibodies that specifically recognize and bind CD276 (also known as B7-H3) with high affinity. These polypeptides and proteins bind both soluble CD276 and CD276 expressed on cell surfaces, with CD276 being expressed or overexpressed on various human tumors and tumor vasculature, including pediatric solid tumors and adult carcinomas such as neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma, prostate, ovarian, colorectal, and lung cancers.
By specifically recognizing and binding CD276, these polypeptides and proteins can target CD276-expressing cancer cells and/or tumor vasculature, potentially eliciting antigen-specific immune responses. The inventive molecules may provide detection of CD276-expressing cancer cells and tumor vasculature, facilitate targeting and destruction of such cells, reduce or eliminate tumor vasculature, and enhance anti-cancer and anti-tumor vasculature responses.
The invention further encompasses chimeric antigen receptors (CARs) incorporating these antigen binding domains, nucleic acids encoding the polypeptides, recombinant expression vectors, host cells including T cells, populations of cells, pharmaceutical compositions, conjugates linking these binding moieties with effector molecules, and kits. The methods involve detecting cancer or tumor vasculature using the inventive materials, as well as treating or preventing cancer and reducing or eliminating tumor vasculature in mammals.
Claims Coverage
The patent includes multiple independent claims mainly focusing on conjugates comprising anti-CD276 binding moieties and recombinant expression vectors encoding these moieties. The key inventive features relate to the specific anti-CD276 binding moieties, their conjugation to effector molecules, and associated compositions and methods.
Anti-CD276 binding moiety conjugated to effector molecule
A conjugate comprising an anti-CD276 binding moiety, specifically comprising the amino acid sequences of SEQ ID NOs: 7 and 8 or SEQ ID NOs: 17 and 18, conjugated to an effector molecule.
Types of anti-CD276 binding moieties
The anti-CD276 binding moiety can be an antibody or antibody fragment, including Fab, F(ab')2, diabody, triabody, tetrabody, single-chain variable fragment (scFv), or disulfide-stabilized variable region fragment (dsFv).
Effector molecule variety
The effector molecule conjugated to the anti-CD276 binding moiety can be one or more of a pyrrolobenzodiazepine (PBD) dimer, drug, toxin, label, small molecule, another antibody, or monomethyl auristatin E (MMAE).
Conjugation linker
The conjugate may further include a linker, which can comprise amino acid sequences SEQ ID NO: 9 or 10, facilitating conjugation between the binding moiety and effector molecule.
Site-specific conjugation technology
The conjugation of the anti-CD276 binding moiety to the effector molecule can be achieved by next-generation site-specific conjugation technologies.
Recombinant expression vectors encoding anti-CD276 binding moieties
Recombinant expression vectors comprising nucleic acids encoding combinations of heavy and light chains SEQ ID NOs: 53 and 54 or SEQ ID NOs: 55 and 56 for expression of anti-CD276 binding moieties.
Host cells and populations of cells with recombinant vectors
Isolated host cells, preferably eukaryotic cells, and populations of such cells comprising the recombinant expression vectors encoding anti-CD276 binding moieties.
Pharmaceutical compositions and kits
Pharmaceutical compositions comprising the conjugates and pharmaceutically acceptable carriers, and kits for treating cancer or reducing tumor vasculature comprising the conjugates, optionally with carriers, printed instructions, or chemotherapeutic agents.
Methods of detecting cancer or tumor vasculature
Methods for detecting presence of cancer or tumor vasculature by contacting cell samples with the described conjugates to form detectable complexes indicative of such presence.
The independent claims focus on conjugates comprising specific anti-CD276 binding moieties conjugated to effector molecules, including the use of linkers and site-specific conjugation methods; recombinant expression vectors encoding these binding moieties; host cells and populations comprising these vectors; pharmaceutical compositions and kits containing these conjugates; and methods for detecting cancer or tumor vasculature using the conjugates.
Stated Advantages
The polypeptides and proteins specifically recognize and bind CD276 with high affinity, targeting cancer cells and tumor vasculature.
The CAR constructs redirect T-cell specificity to CD276-expressing cells in a non-MHC-restricted manner, enhancing immune response.
The conjugates provide targeted delivery of effector molecules such as cytotoxic drugs to CD276-expressing cancer cells and tumor vasculature.
Use of site-specific conjugation enhances precision and efficacy of antibody-drug conjugates.
The inventive materials allow detection of cancer or tumor vasculature by forming detectable complexes with CD276.
Documented Applications
Detecting the presence of cancer or tumor vasculature in a mammal by contacting samples with anti-CD276 polypeptides, proteins, CARs, anti-CD276 binding moieties, or conjugates.
Treating or preventing cancer characterized by expression or overexpression of CD276 in a mammal by administering the anti-CD276 materials.
Reducing or eliminating tumor vasculature in a mammal by administering the anti-CD276 materials.
Use of chimeric antigen receptor T cells expressing anti-CD276 antigen binding domains to target CD276-expressing cancer cells and tumor vasculature.
Use of antibody-drug conjugates targeting CD276 for therapy against a variety of cancers including pediatric solid tumors, adult carcinomas, neuroblastoma, Ewing's sarcoma, prostate, ovarian, colorectal, lung, breast, ovary, colon, and pancreatic cancers.
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