On September 27, 2021 Oblique Therapeutics reported that it has reached a key milestone in its aKRAS antibody program and achieved validation of its Abiprot platform (Press release, Oblique Therapeutics, SEP 27, 2021, https://obliquet.com/wp-content/uploads/2021/09/Oblique-Therapeutics-announces-achievement-of-key-milestone-in-its-aKRAS-mAb-program-and-Abiprot-platform-002.pdf [SID1234590351])

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Oblique Therapeutics has developed a unique, proprietary methodology Abiprot to identify epitopes on targets that have previously proven difficult to address with antibodies. Using this platform, a few epitopes were identified in KRAS, one of which encompassed the frequently mutated amino acids 12 and 13. Interestingly, this epitope is not well exposed in any of the published crystal structure of the protein. Using this epitope, Oblique Therapeutics has developed a number of potent monoclonal antibodies (mAb) that bind G13D, G12D, G12V mutant proteins selectively. Anti-G13D mAbs inhibit proliferation and cause apoptosis in a G13D mutant human colorectal cancer (CRC) cell line. Oblique is now happy to announce that it has seen good efficacy and a high degree of tumor growth inhibition of two of these aG13D mAbs in a mouse xenograft model of G13D human CRC.

This in vivo proof-of-concept is significant from two perspectives. Firstly, this validates the Abiprot platform as an important tool in identifying epitopes and generating functional antibodies against difficult targets of therapeutic interest. Secondly, this provides a high degree of confidence in progressing aG13D mAb (and mAbs against other mutants) into development for treating KRAS G13D mutant CRC and other malignancies.

Prof Owe Orwar, Founder and CEO, Oblique Therapeutics, commented, "We are truly excited by the outstanding promise we see in these results. The team led by Dr. Sreesha Srinivasa and in collaboration with Karolinska Institutet has done an exceptional job in the early phases of developing KRAS-mutant specific antibodies against three major mutations of KRAS, one of which is the driver mutation for pancreatic cancer. The in vivo proof of concept for aG13D mAb means that we will put high priority to advance this program through preclinical development aiming at clinical entry and dosing of the first patient as fast as we ever can"

About KRAS
KRAS which is mutated in approximately 20% of human cancers is the most frequently mutated oncogene. Many of the approved targeted therapies such as EGFR, HER2, RAF inhibitors do not work for KRAS mutated patients in CRC, Lung, Melanoma and other cancers. Thus, there is an urgent need to develop effective therapies for the patients harboring KRAS mutations. Mutations at residues 12 and 13 account for a vast majority of KRAS mutations. Among these, G12D, G12C, G12V and G13D are the more common amino acid substitutions. Lumakras (Amgen) has been recently approved for G12C mutated Lung cancer and another G12C inhibitor from Mirati Therapeutics is in late stages of clinical development. However, there are no drugs approved or in clinical development targeting G12D, G12V and G13D mutations.

About Abiprot
Abiprot, is a proprietary methodology to identify epitopes on protein targets that have previously proven difficult to address with antibodies. Abiprot can identify high-affinity antibody binding sites in a given protein with single amino acid resolution while the protein resides in its native environment. It is based on using a tailored molecular reporter system and proteomics. The platform yields detailed sequence and structure information for epitope identification and development. Oblique Therapeutics is applying this technology for discovery of a new generation of selective antibody therapeutics targeting cancer and pain