National Institutes of Health, a Component of the US Dept. of Health & Human Services

The Dow Chemical Company

Syed V S Kashmiri

Jeffrey Schlom

Eduardo Agustin Padlan

Peter S Mezes

Kimberly S Johnson

Ruth A Richard

Liming Shu

The present disclosure provides humanized CC49 monoclonal antibodies that bind TAG-72 with high binding affinity and that are minimally immunogenic. In one embodiment, a humanized CC49 antibody includes a non-conservative amino acid substitution in a light chain complementarity determining region 3 of the CC49 antibody. In a further embodiment, the humanized CC49 antibody includes a non-conservative substitution of a first residue in a light chain complementarity determining region 3 and a substitution of a second residue in a complementarity determining region of the humanized CC49 antibody. In several of the embodiments, methods are disclosed for the use of a humanized CC49 antibody.

Humanized anti-tag 72 CC49 for diagnosis and therapy of human tumors

Methods to determine immunogenicity of humanized anti-tag 72 CC49 antibodies

The invention is directed towards mouse-human chimeric variants of CC49 monoclonal antibodies with minimal murine content. A first aspect of the invention provides CDR variants of humanized monoclonal antibody (HuCC49) in which less than all six (three heavy chain and three light chain) Complementarity Determining Regions (CDRs) of CC49 are present. A second aspect of the invention provides SDR variants of humanized monoclonal antibody (HuCC49) in which only Specificity Determining Regions (SDRs) of at least one CDR from CC49 are present. The invention is also directed towards biotechnological methods of making the variants and therapeutic methods of using the variants.

Variants of humanized anti-carcinoma MAb CC49

The present disclosure provides humanized CC49 monoclonal antibodies that bind TAG-72 with high binding affinity and that are minimally immunogenic. In one embodiment, a humanized CC49 antibody includes a non-conservative amino acid substitution in a light chain complementarity determining region 3 of the CC49 antibody. In a further embodiment, the humanized CC49 antibody includes a non-conservative substitution of a first residue in a light chain complementarity determining region 3 and a substitution of a second residue in a complementarity determining region of the humanized CC49 antibody. In several of the embodiments, methods are disclosed for the use of a humanized CC49 antibody in the detection or treatment of a tumor in a subject. Also disclosed is a kit including the humanized CC49 antibody described herein.

Nucleic acids encoding humanized anti-tag 72 CC49 antbodies

Humanized anti-TAG-72 CC49 monoclonal antibodies are disclosed herein. The antibodies include a light chain Complementarity Determining Region (L-CDR)1, a L-CDR2, and a L-CDR3; and a heavy chain Complementarity Determining Region (H-CDR)1, a H-CDR2, and a H-CDR3 from humanized antibody HuCC49V10. The L-CDR1, L-CDR2, L-CDR3 are within a HuCC49V10 light chain framework region that includes the corresponding amino acid from LEN at position 5, 19, 21, and 106 in the light chain. The H-CDR1, H-CDR2, and H-CDR3 are within a heavy chain HuCC49V10 framework comprising a human 21/28' CL residue at positions 20, 38, 48, 66, 67, 69, and 80 in the heavy chain. These humanized CC49 antibodies retain binding affinity for TAG-72 and have reduced immunogenicity, as compared to a parental HuCC49V10 antibody. Methods are disclosed herein for using these antibodies in the treatment or diagnosis of a tumor, such as a carcinoma, expressing TAG-72.

Nucleic acid molecules encoding minimally immunogenic variants of SDR-grafted humanized antibody CC49

Minimally immunogenic variants of SDR-grafted humanized antibody CC49 and their use

Humanized anti-tag 72 cc49 for diagnosis and therapy of human tumors

Variants of humanized anti-carcinoma monoclonal antibody CC49

Novel composite and humanized anti-TAG-72 monoclonal antibodies, antibody fragments, and derivatives thereof using human subgroup IV kappa light chain framework regions.

Composite antibodies of humanized human subgroup IV light chain capable of binding to TAG-72

Variants of humanized anti carcinoma monoclonal antibody cc49

Humanized anti-tag-72 monoclonal antibodies using human subgroup 4 kappa light chains

Growing community of inventors

Gaithersburg, MD, United States of America

Syed V S Kashmiri