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Chimeric and humanized antibodies with specificity for the CD33 antigen
M S Co1, N M Avdalovic, P C Caron
1Protein Design Labs, Inc., Mountain View, CA 94043.
Journal of Immunology (Baltimore, Md. : 1950)
|February 15, 1992
Summary
Researchers engineered humanized antibodies targeting the CD33 antigen found on myeloid cells. These novel humanized M195 antibodies demonstrated unexpectedly higher binding affinity to CD33 compared to original mouse or chimeric versions.
Area of Science:
- Immunology
- Biotechnology
- Oncology
Background:
- The M195 monoclonal antibody targets the CD33 antigen, present on normal and leukemic myeloid cells.
- Development of therapeutic antibodies requires optimization for efficacy and reduced immunogenicity.
Purpose of the Study:
- To clone light (L) and heavy (H) chain cDNAs of the M195 antibody.
- To construct mouse/human chimeric and humanized IgG1 and IgG3 antibodies based on M195.
- To evaluate the binding affinity of engineered antibodies to the CD33 antigen.
Main Methods:
- Cloning of M195 antibody L and H chain cDNAs.
- Construction of chimeric antibodies (mouse/human IgG1 and IgG3).
- Engineering of humanized antibodies using M195 complementarity-determining regions (CDRs) and human framework regions, incorporating key framework residues identified via computer modeling.
Main Results:
- Successfully constructed chimeric and humanized M195 antibodies.
- Humanized M195 antibodies exhibited significantly higher apparent binding affinity for the CD33 antigen compared to chimeric or parental mouse antibodies.
- Reshaped variable (V) regions in humanized antibodies contributed to enhanced binding.
Conclusions:
- Humanized M195 antibodies represent an advancement over chimeric versions for targeting CD33.
- Engineered humanized antibodies show improved binding characteristics, potentially enhancing therapeutic applications in myeloid malignancies.
- Computer modeling and CDR-grafting strategies are effective in developing high-affinity humanized antibodies.