Rationally-designed anti-mullerian inhibiting substance type II receptor antibodies
Inventors
Adams, Gregory P. • Simmons, Heidi H. • Robinson, Matthew K. • Dunbrack, Roland • Lehmann, Andreas
Assignees
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Publication Number
US-9611321-B2
Publication Date
2017-04-04
Expiration Date
Abstract
Methods for generating hybrid antibodies are provided.
Core Innovation
The invention relates to hybrid anti-MISIIR antibody designs that are immunologically specific for the Mullerian Inhibiting Substance Type II Receptor (MISIIR). The complementarity determining region 3 (CDR3) of either the light chain or the heavy chain is replaced with a sequence comprising amino acids 533-550 of SEQ ID NO: 5, to generate antibodies that specifically bind MISIIR extracellularly. The designs use MIS ligand-derived loops inserted into CDR3 of heavy and/or light chain to form the hybrid antibodies.
The antibody designs include selectable framework options and antibody formats, including scFv and other antibody fragments. The document describes insertion considerations such as length and orientation of the inserted MIS sequences into CDRs, and framework compatibility with MIS ligand-derived loops. Sequence identity and homology constraints relative to specific SEQ IDs are used to define covered hybrid antibody embodiments.
The hybrid antibodies are further described as being used to modulate MIS signaling associated with MISIIR, including MIS-induced MISIIR signaling blockade and, for an example, agonistic signaling. Hybrid scFvs (RAD-1-0002 and RAD-1-0003) block MIS-induced MISIIR signaling in a reporter gene assay, while RAD-1-0001 can be agonistic.
Claims Coverage
The provided independent claim is clm-00001, which defines an isolated MISIIR-specific antibody with a specified CDR3 replacement sequence. The dependent claims add restrictions and concrete embodiment limitations, including specific covered sequence identities, allowable antibody formats, conjugation categories, and type I receptor-binding agent constitution.
MISIIR-specific isolated antibody with CDR3 replacement by SEQ ID NO: 5 amino acids 533-550
An isolated antibody immunologically specific for Mullerian Inhibiting Substance Type II Receptor (MISIIR), wherein the complementarity determining region 3 (CDR3) of either the light chain or the heavy chain is replaced with a sequence comprising amino acids 533-550 of SEQ ID NO: 5.
CDR3 replacement embodiments including SEQ ID NO: 7, SEQ ID NO: 8, or SEQ ID NO: 9
An antibody (as defined for the MISIIR-specific CDR3-replacement concept) that includes SEQ ID NO: 7, 8, or 9.
Sequence-identity constrained embodiments relative to SEQ ID NO: 7/8/9 (090%)
An antibody having at least 90% sequence identity with SEQ ID NO: 7, 8, or 9.
Covered antibody formats and engineered fragments
An antibody selected from specified antibody formats, including monoclonal and engineered fragments such as scFv, Fab, and F(ab)2/F(ab) fragments.
Conjugation to specified functional molecules (radioisotopes/imaging/therapeutic agents)
An antibody conjugated to one or more functional molecules including radioisotopes and various therapeutic or imaging agents.
Type I receptor-binding agent constitution (antibody or ligand)
A binding agent for a type I receptor is either an antibody that binds the type I receptor or a ligand of the type I receptor.
Across clm-00001 and the provided dependents, the coverage is anchored in an isolated MISIIR-specific antibody defined by CDR3 replacement with SEQ ID NO: 5 amino acids 533-550, with dependent coverage further limited by inclusion of specific SEQ ID embodiments or 090% identity to such sequences, permissible antibody formats/fragments, optional conjugation categories (including radioisotopes and imaging/therapeutic agents), and a constraint that a type I receptor-binding component is an antibody or a ligand.
Stated Advantages
Enables antibodies that specifically bind MISIIR extracellularly.
Can block MIS-induced MISIIR signaling (as shown for example hybrid scFvs).
Can provide agonistic signaling in at least one example hybrid scFv (RAD-1-0001).
Supports imaging/immunodetection and diagnostic/prognosis/risk assessment uses through use of labeled/conjugated agents.
Supports cancer therapy via conjugation to therapeutic payloads including radioisotopes, chemotherapeutic agents, and toxins/immunotoxins.
Supports targeted delivery for gene therapy vehicles (as described in the document context).
Documented Applications
Cancer therapy, including conjugation to radioisotopes, chemotherapeutic agents, toxins/immunotoxins.
Tumor imaging and immunodetection using imaging/contrast labels.
Diagnosis, prognosis, and risk assessment.
Motor neuron disease/neuropathy treatment (as described in the document context).
Targeted delivery for gene therapy vehicles (as described in the document context).
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