Jared Gollob Chief Medical Officer @KymeraTx shares common questions he gets from colleagues such as “What’s Advantage of IRAK 4 Combined into One Molecule?” and others on the AACR 2020 presentation entitled IRAKIMiD Degrader Program and Present Preclinical Data Demonstrating Potent Immunomodulatory and Antitumor Activity for its Novel STAT3 Degraders in Immuno-oncology
Kymera Therapeutics , Inc., a biotechnology company pioneering targeted protein degradation to develop innovative protein degrading medicines for patients, today announced that it will present preclinical data on its potent and highly selective STAT3 degraders, as well as first data from its novel IRAKIMiD degraders combining IRAK4 and IMiD substrate degradation. Data will be discussed during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II on Monday 22 June at 9:00 AM EDT in two separate presentations (Abstracts # 10165 and # 4349, respectively).
STAT3 is an enticing but elusive target known to control the oncogenesis, tumor immune evasion, inflammation, and fibrosis genes involved. STAT3 has been shown to accelerate tumor growth in cancer and encourage an immunosuppressive microenvironmental tumor (TME). Kymera has previously documented the ability of its highly selective STAT3 degraders to achieve tumor regression in STAT3-dependent hematological malignancy models of the mouse xenograft. The company will present preclinical data showing that its STAT3 degraders have down-regulated immune checkpoint signals on tumor cells and positively modulated immune cell composition and function in the TME, leading to in vivo antitumor activity in a refractory solid tumor model compared to standard anti-PD-1 / L1 immunotherapy. These findings show the potential for degraders of STAT3 to drive antitumor responses through both tumor cell-intrinsic and -extrinsic immunomodulation as well as direct antitumor influence.
Kymera will also present the first data from its active IRAKIMiD lymphoma degraders in production for the treatment of MYD88-mutant lymphomas, around one-quarter of all diffuse B-cell lymphomas (DLBCL). IRAKIMiDs are novel heterobifunctional degraders that target IRAK4 and IMiD substrates with a single, small molecule to degrade. Although IRAK4 degradation alone provides a viable therapeutic strategy we believe to be superior to IRAK4 kinase inhibition, aimed at two complementary lymphoma biology pathways address possible tumor escape mechanisms and demonstrate synergistic activity in MYD88-mutant lymphomas compared to IRAK4 degraders or IMiDs alone. In particular, IRAKIMiDs demonstrated improved cell death and activity spectrum relative to IMiDs or IRAK4-selective degraders, and led to significant in vivo tumor regressions in multiple MYD88-mutant B cell lymphoma models that Kymera believes are superior to those observed with other agents such as BTK inhibitors and IMiDs in preclinical studies.
Highlights from the AACR report
ABSTRACT # 10165 / POSTER # LB-088, “A STAT3 selective targeted protein degrader reduces the immune-suppressive tumor microenvironment and induces antitumor activity in preclinical models,” Fred Csibi, PhD, Associate Director of Oncology Biology at Kymera Therapeutics presented.
· KTX-201 (formerly referred to as KYM-003) is a potent and highly selective degrader of STAT3 with immune and tumor cell involvement.
· Degradation of KTX-201 STAT3 in both immune and tumor cells reversed gene expression which contributes to immune suppression.
· KTX-201 therapy resulted in the reversal of immunosuppression in a model of non-small cell lung cancer in vitro and antitumor activity in a model of colorectal mouse cancer resistant to immune control point inhibitors.
ABSTRACT # 4349 / POSTER # 5222, “Degraders targeting both IRAK4 and IMiD substrates demonstrate combinatorial effects leading to wider activity with long-lasting and full regression in MYD88 mutant xenografts in vivo,” by Duncan H. Walker, PhD, VP of Oncology at Kymera Therapeutics.
· IRAK4 degradation, but not inhibition of IRAK4 kinase, showed in vitro additive and synergistic activity with IMiDs; IRAKIMiDs combining these activities in a single molecule showed effective in vitro and in vivo activity.
· Degradation of both IRAK4 and IMiD substrates associated with in vitro cell growth inhibition, a prerequisite for both cell death activities.
· Regressions observed in MYD88-mutant lymphoma xenograft models were correlated with degradation of both IRAK4 and IMiD substrates, in line with the dual-targeting activities of these molecules;