CD33 Antibodies Targeting CD33D2 Isoform
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Solution Overview
Problem
Current CD33-directed immunotherapies, such as gemtuzumab ozogamicin, are ineffective for patients expressing the CD33D2 isoform due to reliance on binding to the IgV domain, necessitating the development of alternative strategies for targeting CD33D2-expressing cancer cells.
Innovation Solution
Development of antibodies and antigen binding fragments that specifically bind to the CD33D2 isoform, including adaptable cell engagers (ACEs) and bispecific T cell engagers (BiTEs), which are designed to target CD33D2-expressing cancer cells and enhance T cell-mediated cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current CD33-directed immunotherapies (e.g., gemtuzumab ozogamicin) are used, then they effectively treat patients with CD33 expressing the wild-type allele, but they show no clinical benefit for patients expressing the CD33D2 isoform due to the splicing variant lacking the IgV domain
Solution Approach 1:
The patent applies local quality by designing antibodies with specific binding characteristics tailored to different CD33 isoforms. The anti-CD33 antibodies are engineered to recognize either the IgV domain (for wild-type CD33) or alternative epitopes (for CD33D2 isoform), allowing each antibody to have optimized local binding properties for its target isoform structure
Solution Approach 2:
The patent achieves universality by developing a family of anti-CD33 antibodies that can bind to multiple CD33 isoforms including both wild-type and CD33D2 variants. This multi-functional antibody family allows a single therapeutic platform to serve multiple patient populations with different CD33 genotypes, making the therapy universally applicable across diverse genetic backgrounds
2Measurement precision
If antibodies targeting the IgV domain are used, then they bind effectively to wild-type CD33, but they cannot bind to CD33D2 isoform which lacks the IgV domain
Solution Approach 1:
The patent applies segmentation by dividing the CD33 targeting approach into distinct antibody specificities: one segment targets the IgV domain for wild-type CD33, while another segment targets alternative epitopes for CD33D2 isoform. This segmentation allows each antibody to maintain high binding specificity for its intended target while collectively covering multiple isoforms
Solution Approach 2:
The patent transitions from a single-dimension binding approach (IgV domain only) to a multi-dimensional approach by identifying and targeting alternative epitopes on CD33D2 that compensate for the missing IgV domain. This dimensional expansion in epitope selection enables binding to isoforms previously inaccessible to IgV-specific antibodies
Data Source
AI summary
Aspects of the disclosure relate to compositions and methods for treating certain (e.g., CD33-positive) cancers. In some aspects, the disclosure provides antibodies that specifically bind to CD33 protein variants that lack an IgV domain. In some aspects, the disclosure provides adaptable cell engagers (ACEs) and recombinant proteins (e.g., BiTEs) comprising an anti-CD33 antibody of the disclosure and an anti-CD3 antibody. In some embodiments, the disclosure provides methods of treating cancer by administering the antibodies, ACEs, or recombinant proteins (e.g., BiTEs) to a subject in need thereof.