The study proposed here seeks to develop efficacious new therapeutic agents for the treatment of cancer. We hypothesize that through the combination of chemistry and an immune effector we can prepare a versatile and effective new class of immunotherapeutics, chemically programmed antibodies or cpAbs. During the first funding period of this grant, we demonstrated that small molecule ligands could be used to effectively program the catalytic antibody 38C2 to target tumors and their supporting vasculature. cpAbs were shown to be effective therapeutics in xenografted human melanoma and breast cancer models as well as syngeneic murine melanoma and colon cancer models. Here we aim to significantly increase the scope of the chemically programmed antibody approach. We will develop versatile and effective linker chemistries that will allow cpAbs to be adapted to work with virtually any combinations of small molecules, peptides, nucleic acids ligands and shRNAs. We hypothesize that the cpAb approach can endow each of these classes of molecules with characteristics that make them more effective cancer therapeutics. We will use these linkers to prepare multifunctional cpAbs that can attack cancers through multiple modes of action such as engaging tumor associated antigens and neutralizing proangiogenic cytokines to selectively kill tumors. We hypothesize that antiangiogenic therapy might be more effective and engender fewer side effects if it can be localized to the tumor site. We further hypothesize that multifunctional cpAbs that simultaneously address tumor associated receptors as well as angiogenic factors will be more potent and broadly applicable therapeutic agents. Given the relevance of our targets in melanoma, breast, colon, ovarian, and head and neck cancers and in angiogenesis in general, successful development of this approach may have many benefits. With multifunctional cpAbs, we will address the therapeutic potential and mechanism of treating cancer in animal models with single cpAbs that target two or more receptors and neutralize proangiogenic cytokines while addressing the question of whether there is a synergistic or additive advantage of combining anti-angiogenic and tumor targeted immunotherapies in cancer. It is anticipated that the results of this work will provide a promising new approach to the treatment of cancer.
Targeted protein therapeutics are promising but costly drugs that are often effective for only a small portion of affected cancer patients. We aim to create a new class of programmable protein therapeutics that will have increased therapeutic breadth, potency, and safety. By creating single drugs that act like drug combinations, we hope that this approach will also be more cost effective.
| Wuellner, Ulrich; Gavrilyuk, Julia I; Barbas 3rd, Carlos F (2010) Expanding the concept of chemically programmable antibodies to RNA aptamers: chemically programmed biotherapeutics. Angew Chem Int Ed Engl 49:5934-7 |
| Popkov, Mikhail; Gonzalez, Beatriz; Sinha, Subhash C et al. (2009) Instant immunity through chemically programmable vaccination and covalent self-assembly. Proc Natl Acad Sci U S A 106:4378-83 |
| Gavrilyuk, Julia I; Wuellner, Ulrich; Barbas 3rd, Carlos F (2009) Beta-lactam-based approach for the chemical programming of aldolase antibody 38C2. Bioorg Med Chem Lett 19:1421-4 |
| Gavrilyuk, Julia I; Wuellner, Ulrich; Salahuddin, Syed et al. (2009) An efficient chemical approach to bispecific antibodies and antibodies of high valency. Bioorg Med Chem Lett 19:3716-20 |
| Sinha, Subhash C; Das, Sanjib; Li, Lian-Sheng et al. (2007) Preparation of integrin alpha(v)beta3-targeting Ab 38C2 constructs. Nat Protoc 2:449-56 |
| Popkov, Mikhail; Rader, Christoph; Gonzalez, Beatriz et al. (2006) Small molecule drug activity in melanoma models may be dramatically enhanced with an antibody effector. Int J Cancer 119:1194-207 |
| Guo, Fang; Das, Sanjib; Mueller, Barbara M et al. (2006) Breaking the one antibody-one target axiom. Proc Natl Acad Sci U S A 103:11009-14 |
