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Antibody Drug and Target Discovery for Cancer Therapy

Christoph Rader was trained in antibody engineering in the lab of his postdoc mentor, the late Carlos F. Barbas III (TSRI, La Jolla, CA) [91], where he initially focused on the development of innovative phage display technologies for the de novo generation, humanization, and affinity maturation of monoclonal antibodies (mAbs). At that time, the first mAbs for cancer therapy (rituximab in 1997 and trastuzumab in 1998; see below for an updated list of FDA-approved and currently marked mAbs for cancer therapy) were approved by the FDA, triggering an immense interest in implementing phage display to broaden and strengthen this emerging class of targeted therapeutics. Since becoming an independent principal investigator, he has continued to make key contributions to applying and refining phage display. Phage display vectors (including pC3C), libraries, and protocols developed in the Rader lab are widely used in laboratories in academia, government, and industry.

One of the remaining challenges of antibody therapeutics in cancer is finding suitable targets that permit potent and safe intervention. The Rader lab identified the receptor tyrosine kinase ROR1 as a novel candidate target for antibody therapeutics in cancer [52], prompting major efforts in academia, government, and industry on translating ROR1 targeting from preclinical to clinical investigations. Its antibody target discovery and validation efforts have since expanded from ROR1 to ROR2 [115] and include a wide variety of cancer indications that express either or both receptor tyrosine kinases on the cell surface. In other target discovery efforts, the Rader lab generated the first antibody library from a patient following allogeneic hematopoietic stem cell transplantation as an innovative tool for concerted antibody drug and target discovery [62]. Phage display strategies are continuously refined for selection against cancer cell lines and primary cancer cells with the objective to discover druggable antibody targets.

The generation and characterization of mAbs prior to their conversion to other therapeutic antibody formats has been a central activity of all three labs Rader led as principal investigator at TSRI (La Jolla, CA, and Jupiter, FL) and NCI, NIH (Bethesda, MD). The antibody drug discovery and validation efforts are based on phage display technology as described above as well as novel mammalian cell display technologies. ROR1-targeting mAbs that were generated in the Rader lab [75] and subsequently converted to chimeric antigen receptors (CARs) [85] completed advanced preclinical investigations in nonhuman primates [96] and commenced clinical trials at the Fred Hutchinson Cancer Research Center (Seattle, WA) in 2016 (NCT02706392).

Building on the Rader lab’s expertise in antibody engineering, it established a reputation for the development of conceptually novel site-specific antibody conjugation technologies. As one of the inventors of chemically programmed antibodies [33] (U.S. Patent 8,252,902), a technology that was acquired by Pfizer and thus far investigated in eight phase I and II clinical trials using a humanized mAb generated by Rader [34], the Rader lab has continued to advance chemically programmed antibodies that utilize amino acid residues with unique chemical reactivity for site-specific conjugation of small synthetic molecules. Chemically programmed antibodies combine a variable synthetic component that serves as targeting moiety with an invariable antibody component that serves as carrying moiety. In addition to blending favorable features of small synthetic molecules and mAbs, chemically programmed antibodies are economically attractive because they utilize the same mAb for an almost unlimited number of target molecule specificities, reducing manufacturing costs and shortening drug discovery and development time [88]. A key advance (U.S. Patent 8,916,159) of the Rader lab at the NCI, NIH (Bethesda, MD) was the demonstration that the 21st natural amino acid selenocysteine can be incorporated into antibody molecules and utilized for the generation of a new class of chemically programmed antibodies [54]. More recently, the Rader lab expanded the concept of chemical programming to bispecific antibodies that recruit and activate cytotoxic T cells [82] [106].

Since rejoining TSRI (Jupiter, FL) in 2012, a major focus of Rader and his team has been on the development of site-specific antibody-drug conjugates (ADCs) for cancer therapy. As part of these efforts, the selenocysteine technology was applied to the bioorthogonal conjugation of highly cytotoxic drugs to antibody molecules [93] [113]. New selenocysteine and cysteine conjugation chemistries that provide superior stability in human serum were established and combined [102] [108]. Furthermore, ADCs in dual variable domain (DVD) format that combine a targeting mAb in the outer Fv with a catalytic mAb in the inner Fv afforded site-specific lysine conjugation [117]. Fueled by its track record at the interface of biology and chemistry, the Rader lab established close collaborations with chemists at TSRI and NCI, NIH with the goal of designing, synthesizing, and testing new linkers and drugs as components of next-generation ADCs. Given the challenges and limitations of clinically investigated and marketed first-generation ADCs with respect to potency and safety, it is anticipated that these most recent efforts will also lead to Investigational New Drug (IND) applications, ultimately providing better treatment options for cancer patients.

 

 

FDA-Approved and Currently Marketed mAbs for Cancer Therapy

(Last update:  October 26, 2017; mAbs generated by phage display technology are marked in blue)

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