Studies In Cynomolgus Monkeys Research Articles

Preclinical pharmacology characterization of HX009, a novel PD1 x CD47 Bi-specific antibody

Certain immune-checkpoint inhibitors have a narrow therapeutic window (TW) as cancer therapeutics, and engineered dual-/multi-targeting agents could potentially widen the TW to bring true clinical benefits. We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. This resulted in an IgG4-based “2 × 2” symmetric structure but with an intentionally-reduced CD47-binding affinity, suggesting a novel candidate cancer immunotherapy. Specifically, HX009 has binding affinity constant of 8.951 × 10–9 M for human PD1 and 2.557 × 10–8 M for human CD47, respectively, where the CD47 binding is significantly weaker as compared to the binding affinity of HX008 to PD1 as well as the binding affinity of SIRPα-Fc to CD47, leading to little binding to RBCs and platelets and is contrasting to many CD47-agents in development. However, HX009 effectively and simultaneously binds to the PD1 and CD47 on PD1+CD47+ T-cells via cis-binding and elicits enhanced T cell activation compared to the parental HX008. HX009 caused little cytokine-release in human peripheral blood mononuclear cells. HX009 cross-species binds to cynomolgus monkey PD1/CD47 but not to rodents, making cynomolgus monkeys the choice of species to investigate the pharmacokinetics (PK) and toxicology of HX009. HX009’s anti-tumor activities were confirmed in several humanized preclinical mouse models by determining either its anti-PD1 (humanized hu-CD47-MC38 models) or anti-CD47 (HuT-102 lymphoma CDX and three PDX-AML models) functions, although limited available humanized models have hindered broadly demonstration of enhanced anti-tumor activities contributed from the dual targeting of the BsAb. The expanded DLBCL-PDX trial data suggested that both EBV-status and OX40 expression could potentially be two positive predictors for response to HX009. An intravenous (IV) infusion PK study in cynomolgus monkey revealed its largely vasculature distribution, terminal half-life (T1/2) of ~ 50 h, and dose-proportional exposure without accumulation. The anti-drug antibody (ADA) was observed in all monkeys as expected, affecting the PK parameters of repeated administration. The IV single-dose toxicology study with a 14-day observation revealed a maximum tolerated dose of 150 mg/kg, while the repeated-dose (once weekly for 4 weeks, 5 doses in total) study showed a highest non-severely toxic dose (HNSTD) of 15 mg/kg. The desired preclinical PK and safety profiles, along with its antitumor activity, support HX009’s candidacy for its clinical development.

Nonclinical Similarity of the Biosimilar Candidate ABP 938 with Aflibercept Reference Product.

ABP 938 is being developed as a biosimilar to Eylea® (aflibercept reference product [RP]), an anti-vascular endothelial growth factor (VEGF) drug used in the management of retinal diseases. Previously, a comparative analytical similarity assessment demonstrated that ABP 938 and aflibercept RP have the same amino acid sequence and exhibit similar higher-order structure and biological activity. The nonclinical studies described here were designed to assess the in vitro pharmacology and the in vivo pharmacokinetics (PK), toxicokinetics (TK), and safety profiles of ABP 938 compared to aflibercept RP. In vitro target-binding kinetics and affinity for VEGF-A and placental growth factor (PIGF) isoforms were evaluated using surface plasmon resonance (SPR). Effector functions were assessed by cell-based assays. PK was evaluated in a nonterminal intravitreal (IVT) ocular distribution study in rabbits. Safety was assessed in a 1-month IVT study in cynomolgus monkeys. SPR results demonstrated that ABP 938 is similar to aflibercept RP in binding kinetics and affinity for VEGF-A111, VEGF-A121, VEGF-A165, VEGF-A189, PlGF-1, and PlGF-2 isoforms. No antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity was observed with ABP 938 and aflibercept RP. Results from thenonterminal ocular distribution study in rabbits indicated that there were no meaningful differences in the distribution kinetics between intravitreally injected ABP 938 and aflibercept RP. Additionally, there was no evidence of ocular or systemic toxicity associated with IVT administration of ABP 938 in a repeat-dose, 1-month toxicology study in cynomolgus monkeys; toxicokinetic and toxicology profiles were similar to aflibercept RP. This integrated assessment of results from the in vitro pharmacology assessment and in vivo PK and TK/toxicology profiles formed the nonclinical portion of the totality of evidence demonstrating ABP938 is a biosimilar to aflibercept RP.

Synthesis, preclinical assessment, and first-in-human study of [18F]d4-FET for brain tumor imaging.

Tumor-to-background ratio (TBR) is a critical metric in oncologic PET imaging. This study aims to enhance the TBR of [18F]FET in brain tumor imaging by substituting deuterium ("D") for hydrogen ("H"), thereby improving the diagnostic sensitivity and accuracy. [18F]d4-FET was synthesised by two automated radiochemistry modules. Biodistribution studies and imaging efficacy were evaluated in vivo and ex vivo in rodent models, while metabolic stability and radiation dosimetry were assessed in non-human primates. Additionally, preliminary imaging evaluations were carried out in five brain tumor patients: three glioma patients underwent imaging with both [18F]d4-FET and [18F]FET, and two patients with brain metastases were imaged using [18F]d4-FET and [18F]FDG. [18F]d4-FET demonstrated high radiochemical purity and yield. PET/MRIin rodent models demonstrated superior TBR for [18F]d4-FET compared to [18F]FET, and autoradiography showed tumor margins that correlated well with pathological extents. Studies in cynomolgus monkeys indicated comparable in vivo stability and effective dose with [18F]FET. In glioma patients, [18F]d4-FET showed enhanced TBR, while in patients with brain metastases, [18F]d4-FET displayed superior lesion delineation compared to [18F]FDG, especially in smaller metastatic sites. We successfully synthesized the novel PET radiotracer [18F]d4-FET, which retains the advantageous properties of [18F]FET while potentially enhancing TBR for glioma imaging. Preliminary studies indicate excellent stability, efficacy, and sensitivity of [18F]d4-FET, suggesting its potential in clinical evaluations of brain tumors. ChiCTR2400081576, registration date: 2024-03-05, https://www.chictr.org.cn/bin/project/edit?pid=206162.

Ticagrelor modestly raises plasma riboflavin concentration in humans and inhibits riboflavin transport by BCRP and MRP4.

Riboflavin (vitamin B2) has been proposed as a biomarker for breast cancer resistance protein (BCRP) activity. In recent studies in mice, cynomolgus monkeys, and humans, BCRP-inhibiting drugs increased the plasma concentration of riboflavin. We showed recently that ticagrelor inhibits BCRP and raises the plasma concentrations of the BCRP substrate rosuvastatin in healthy volunteers. In the same drug-drug interaction study, we now investigated whether ticagrelor affects the plasma concentrations of riboflavin. Intake of 90 mg ticagrelor increased the ratio between the peak plasma riboflavin concentration and the fasting riboflavin concentration before ticagrelor administration by 1.20-fold (90% confidence interval, 1.10-1.32; P = 0.006) compared to placebo. In vitro, riboflavin was transported by BCRP and multidrug-resistance-associated protein 4 (MRP4) but no clear transport was observed by MRP2, MRP3, or the P-glycoprotein. Moreover, ticagrelor inhibited the transport of riboflavin in BCRP- and MRP4-expressing membrane vesicles with unbound 50% inhibitory concentrations of 0.020 and 1.1μM, respectively. Based on vesicle and tissue protein expression data, the small intestinal MRP4-mediated efflux clearance of riboflavin (1.2-1.4 nL/min/mg) was estimated to be similar to that mediated by BCRP (0.23-1.3 nL/min/mg). As MRP4 is expressed in the basolateral membrane of enterocytes, it may facilitate the absorption of riboflavin and impair the utility of riboflavin as a biomarker of intestinal BCRP. To conclude, ticagrelor modestly raises the plasma concentration of riboflavin probably by inhibiting intestinal BCRP. Inhibition of intestinal MRP4 may have reduced the absorption of riboflavin and limited the effect of ticagrelor on riboflavin levels.

The novel and potent CD40 agonist KHK2840 augments the antitumor efficacy of anti-PD-1 antibody and paclitaxel.

Lack of tumor-reactive cytotoxic T lymphocytes (CTLs)limits the antitumor efficacy of immune checkpoint inhibitors (ICIs). CD40 agonists have been expected to overcome this limitation by generating tumor-reactive CTLs. However, the clinical efficacy of CD40 agonistic antibodies is not as good as in non-clinical studies. The novel human CD40 (hCD40) agonist KHK2840 is a fully human anti-CD40 IgG2 agonistic antibody that is Fc-engineered to minimize complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Compared to other hCD40 agonists, KHK2840 exhibited the most potent hCD40 agonistic signal in tumor-bearing hCD40 transgenic mice and human peripheral blood B cells. Moreover, KHK2840 enhanced the antitumor efficacy of the antiprogrammed cell death 1 antibody and paclitaxel. Comprehensive immune profiling revealed that the antitumor immune response of the triple combination involved tumor-draining lymph nodes in addition to tumor microenvironments. This suggests that a coordinated antitumor immune response between tumors and lymph nodes may underlie the synergistic antitumor efficacy of the triple combination therapy. Finally, a toxicology study in cynomolgus monkeys demonstrated that KHK2840 activated the CD40 signal with tolerable toxicological properties. These results indicate that KHK2840 is a novel and potent hCD40 agonistic antibody for cancer immunotherapy, which is expected to augment the antitumor efficacy of ICIs and chemotherapy.

P10-13 Special considerations in conducting an enhanced preand postnatal development (ePPND) study in cynomolgus monkeys of biotherapeutics

P10-13 Special considerations in conducting an enhanced preand postnatal development (ePPND) study in cynomolgus monkeys of biotherapeutics

A generic anti-drug antibody assay for monoclonal antibody therapeutics with broad dynamic range eliminates the need for titer evaluation in preclinical studies

In preclinical protein therapeutic development studies, the emergence of anti-drug antibodies (ADA) can potentially impact drug pharmacokinetics and safety. While immunogenicity assessment is not mandatory in preclinical studies, banking samples can be valuable for interpreting unexpected pharmacological responses. Immunoassays that use generic reagents across different drug molecules can simplify ADA assessment and expedite sample evaluations. This work showcases the ability of the Gyrolab automated immunoassay platform to detect and quantify both drug-free and drug-bound (total) ADAs to monoclonal antibody (mAb) therapeutics in cynomolgus monkey preclinical studies. Compared to the previously reported total ADA ELISA, the Gyrolab assay exhibited a wider signal dynamic range and increased drug tolerance. Similar sensitivity, dynamic range and cut point factors were observed for four therapeutic mAbs of different isotypes using the Gyrolab assay. Here we present a comparison of ADA assays using bridging ELISA, total ADA ELISA and total ADA Gyrolab formats in a cynomolgus monkey study where the subjects were treated with a single dose of a mAb therapeutic. We demonstrate that the total ADA assays detected host ADA responses at earlier time points compared to the bridging ELISA. The Gyrolab assay has the best correlation between signal-to-noise (S/N) and titer over a wide ADA concentration range, highlighting the utility of Gyrolab in S/N reporting of ADA response to eliminate the need for secondary titer assays. Collectively, our results demonstrate that the generic ADA Gyrolab assay minimizes the necessity for extensive assay development and optimization for therapeutic mAbs, streamlining preclinical immunogenicity assessment to enable interpretation of pharmacological data.

20-Week intramuscular toxicity study of rotigotine behenate extended-release microspheres for injection via intramuscular injection in cynomolgus monkeys

Continuous dopaminergic stimulation (CDS) has become an important strategy for the development of drugs to treat Parkinson's disease (PD). Rotigotine behenate extended-release microspheres (RBEM) for injection represents a new treatment regime for CDS and is being applied for clinical trial. Our study in cynomolgus monkeys was a 20-week repeat dose toxicity investigation with RBEM at dosages of 90, 180, 360, with a 12-week recovery period. The results observed some irritations in the application site and surrounding tissues in Placebo microspheres and each dose of RBEM, was accompanied with increased white blood count and fibrinogen. RBEM-treated monkeys were additionally noted with a pharmacological action-related decrease in prolactin. These findings showed certain reversibility after the 12-week recovery phase. No clear sex difference was noted in the plasma exposure to rotigotine. The exposure generally increased in a dose-proportional manner. In summary, major toxicological effects are associated with the dopamine agonist-related properties of rotigotine, and the removal of foreign bodies caused by p oly (lactide-co-glycolide) (PLGA)and sodium carboxymethyl cellulose (SCMC), and the no-observed-adverse-effect-level (NOAEL) was 360 mg/kg.

Preclinical characterization of a novel investigational monoclonal antibody CM313 with potent CD38-positive cell killing activity.

CM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb. The binding of CM313 to CD38 recombinant protein across species was assessed using ELISA. The binding of CM313 to CD38-positive (CD38+) cells was detected using flow cytometry assays. CM313-induced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis on different CD38+ cells were assessed by LDH release assays or flow cytometry assays. The effect of CM313 on CD38 enzymatic activity was measured using fluorescence spectroscopy. CM313 immunotoxicity in human blood was assessed using flow cytometry assays, ELISA, and LDH release assays. Anti-tumor activity of CM313 was assessed in multiple mouse xenograft models. Safety profile of CM313 were evaluated in cynomolgus monkeys and human CD38 transgenic (B-hCD38) mice. There exist unique sequences at complementarity-determining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38+ cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38. However, CM313 showed more potent CDC than isatuximab. In vivo, CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or off-target risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly. CM313 is a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.

Abstract LB448: VBC103: An innovative Trop2/Nectin4 targeted bispecific antibody drug conjugate (ADC) in bladder urothelial carcinoma (UC), triple-negative breast cancer (TNBC) and beyond

Abstract Trop2 and Nectin4 are transmembrane proteins involved in cancer pathogenesis. The therapeutic potential of targeting Trop2 or Nectin4 has been demonstrated through the approval of Trodelvy™ (Sacituzumab govitecan; SG) and Padcev™ (Enfortumab Vedotin; EV). However, the clinical use of these agents is accompanied by safety concerns. Trodelvy carries Boxed Warnings for severe or life-threatening neutropenia and severe diarrhea, while Padcev is associated with serious skin reactions. These safety issues underscore the importance of improving the drugs' safety profiles. It should be noted that the co-expression of Trop2 and Nectin4 is high in solid tumors while limited or moderate in normal tissues, presents an opportunity for more tumor-specific targeting and supports the bispecific design that could potentially address these safety issues. VBC103 is a bispecific antibody-drug conjugate (ADC) that selectively targets both Trop2 and Nectin4, which are highly co-expressed in UC, TNBC and other tumors. It delivers a TOPOi payload with a strong bystander effect to tumor cells. Our unique design maximizes efficacy while minimizing safety concerns. VBC103 has the following features to differentiate itself from other drugs targeting Trop2 or Nectin4 separately in clinical development and on the market. 1. Modulated affinity and valency. VBC103 incorporates a moderate affinity arm that targets Trop2 and a moderate affinity but high avidity arm that targets Nectin4, allowing for enhanced binding avidity, internalization, and cytotoxicity compared to its parental molecules (anti-Nectin4 parental antibody) or approved drug like EV. Additionally, the moderate affinity of both Trop2 and Nectin4 in VBC103 helps to reduce target-driven toxicities in normal tissues. 2. Innovative format of VHH-Fc fusion protein (MW 90kDa) demonstrated the superior tumor penetration, accumulation (MFI ratio in tumor: 280 VS 174) and distribution (MFI ratio in liver: 10 VS 18) compared to the IgG1 mAb- enfortumab (MW 150kDa). 3. Stronger bystander cell killing effect of the TOPOi payload vs. that of the payload used in EV. 4. Superior in vivo efficacy. In the UC CDX model, TGI 95% [VBC103, 5 mpk] vs 77% [EV, 8 mpk] vs 70% [EV+SG, 4+4 mpk] (Q3W X 3; ADC molecular equivalence) at Day 42 post injection. In the TNBC CDX model, VBC103 demonstrated continued superior efficacy compared to EV (maximum tolerated dose) and SG when administered as a single dose treatment at Day 21 post injection. 5. Wide therapeutic widow (TW). Preliminary toxicity studies in cynomolgus monkeys demonstrated good tolerability of repeated doses (18 and 36 mpk) of VBC103, which is molecular equivalent to 30 and 60 mpk of IgG1 ADC. These findings could establish a TW of >10 (HNSTD/MED). 6. Good developability. VBC103 also exhibited excellent developability based on plasma stability and other stress test data, which suggests it a good candidate in future CMC development. In summary, VBC103, with its unique bispecific design and differentiated features in affinity, valency, linker-payload, has shown promising potential as a first-in-class ADC candidate. Discovery studies have revealed favorable efficacy and toxicity profiles, supporting advancing VBC103 into clinical trials. Citation Format: Wei Wang, Jing Li, Lingyu Guan, Man Xu, Qun Yin. VBC103: An innovative Trop2/Nectin4 targeted bispecific antibody drug conjugate (ADC) in bladder urothelial carcinoma (UC), triple-negative breast cancer (TNBC) and beyond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB448.

Abstract LB438: Preclinical characterization of ONM-412, an ultra-pH sensitive nanoparticle encapsulated IL-12 fusion protein

Abstract Background: Interleukin-12 is a potent pleiotropic cytokine, but its clinical translation has been hindered by toxicities. To deliver IL-12 to tumors with high spatial and temporal precision while minimizing off-tumor effects, we have developed an ultra-pH sensitive nanoparticle platform - ON-BOARD - that shields payloads from systemic exposure and targets solid tumors by responding to tumor acidity. Herein, we report the preclinical efficacy and safety characterization of ONM-412, an ON-BOARD nanoparticle encapsulated IL-12Fc fusion protein, and muONM-412, an encapsulated murine IL-12Fc. Methods: Properties and stability profiles of ONM-412 were characterized. pH-specific bioactivity was determined in cell-based reporter and IFNγ induction assays while the activation of ONM-412 was compared to a protease-cleavable IL-12 prodrug. Efficacy and tolerability of muONM-412 were studied in vivo after intravenous injection in mice. Pharmacodynamic response was evaluated by measuring cytokine levels in plasma and tissue, and the changes in tumor immune microenvironment were characterized. Toxicity was measured by body weight loss, systemic cytokine levels and clinical chemistry. Anti-tumor efficacy of muONM-412 was evaluated in MC38 tumor-bearing mice. The safety and tolerability of ONM-412 is also undergoing evaluation in a toxicology study with cynomolgus monkeys. Body weight, hematology, clinical chemistry and urine analysis were performed. Results: ONM-412 showed high encapsulation efficiency (>85%) in uniformly distributed particles (Dh<50nm) with 6-month on-going shelf-life stability. pH-specific release was confirmed in vitro with a >100-fold activation window between the acid-activated and intact formulations by an HEK reporter assay and an IFNγ induction assay. ONM-412 showed rapid and complete recovery of IL-12 bioactivity in <10 minutes after acid-activation while MMP demasking of a prodrug required overnight incubation and compromised potency. In vivo, mice treated with muONM-412 demonstrated significantly improved tolerability compared to unencapsulated IL-12Fc: body weight loss was reduced, no liver toxicity was observed, and plasma IFNγ levels were >1,000-fold lower. muONM-412 induced tumor immune remodeling, with increased infiltration by IFNγ+ and GzmB+ CD8 T and NK cells, and demonstrated strong dose-responsive anti-tumor efficacy in MC38 tumor-bearing animals. Preliminary results from an on-going study in cynomolgus monkeys suggest ONM-412 is well-tolerated at equivalent doses to those that induced maximum antitumor response in mice. Conclusions: ONM-412 significantly improved tolerability over unencapsulated IL-12Fc and showed potent anti-tumor efficacy in mice. It was well-tolerated in mice and non-human primates, showing potential for clinical translation. Citation Format: Qingtai Su, Stephen Gutowski, Austin Burcham, Bhargavi Allu, Zirong Chen, Fiona Stavros, Ruolan Han, Jason B. Miller, Tian Zhao. Preclinical characterization of ONM-412, an ultra-pH sensitive nanoparticle encapsulated IL-12 fusion protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB438.

Abstract 1865: HDP-102 - a CD37-targeting Amanitin-based-ADC for the treatment of NHL - non-clinical data package

Abstract Background: Antibody-drug conjugates (ADC) are gaining importance as anti-cancer therapy. Most ADCs are based on cytotoxic warheads targeting only proliferating cells. In contrast, HDP´s proprietary ATAC platform utilizes amatoxins as payload. Amatoxins are specific inhibitors of eukaryotic RNA polymerase II, suppressing a key function in the protein metabolism not limiting their cytotoxicity to proliferating cells. Furthermore, there are no known resistance mechanisms against amatoxins in mammalian cells (i.e. multi drug resistance transporters), making ATACs a promising new class of anti-cancer ADCs. Here we present pre-clinical data on the anti-CD37 ATAC HDP-102. CD37 is a transmembrane protein expressed exclusively on immune cells, mainly mature B-cells, and in many B-cell malignancies, including Non-Hodgkin’s Lymphoma (NHL). Material and Methods: HDP-102: anti-CD37 ADC based on cysteine-reactive, site-specific amatoxin-linker constructs produced by HDP Cytotoxicity assays: CellTiter Glo 2.0 (Promega) assays on CD37pos cell lines MEC-2, Raji-luc, Ramos and CD37neg Nalm-6 cells Efficacy studies: Disseminated MEC-2 and Raji-Luc mouse xenograft tumor models in single dose experiments Tolerability study in Cynomolgus monkeys: i.v. HDP-102 treatment on days 1 and 22; blood sampling for PK analysis; necropsy and histopathology on days 28 and 64 Results: HDP-102 showed full-blown cytotoxicity with EC50 values in the low nanomolar range in all CD37pos cell lines in vitro but no cytotoxicity on CD37neg cells. In vivo, the anti-tumor efficacy of HDP-102 was evaluated in disseminated CDX models of NHL. A single dose of 0.5 mg/kg HDP-102 already led to complete tumor remission in all animals in a Raji-luc model and 60% survival on day 100 in a MEC-2 model, demonstrating the high potency of HDP-102 in NHL models. In a tolerability study in Cynomolgus monkeys, i.v. administration of HDP-102 was well tolerated up to 2.5 mg/kg without clinical signs of toxicity. Microscopically, decreased cellularity in lymphoid tissue was the main finding, caused by the targeted effect of HDP-102 on CD37pos cells. The HNSTD of 2.5 mg/kg together with the potent anti-tumor efficacy of HDP-102 leads to a therapeutic window of ~200 for HDP-102. Conclusion: CD37 is an ideal target for ADCs due to its high prevalence in B-cell malignancies and limited expression on healthy cells. We have demonstrated that the anti-CD37 ATAC HDP-102 is a promising drug candidate for the treatment of NHL. HDP-102 showed excellent anti-tumor efficacy in CDX models even after single doses. Pharmacological activity of HDP-102 was also seen in Cynomolgus monkeys as evidenced by depletion of B-cells in lymphoid organs. Furthermore, HDP-102 was well tolerated in monkeys. Taken together, based on pre-clinical data, HDP-102 is a promising new treatment option for NHL patients combining a good safety profile with strong anti-tumor efficacy. Citation Format: Sarah-Jane Neuberth, Kristin Decker, Christian Orlik, Irina Dranova, Anikó Pálfi, Torsten Hechler, Andreas Pahl, Michael Kulke. HDP-102 - a CD37-targeting Amanitin-based-ADC for the treatment of NHL - non-clinical data package [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1865.

Abstract 2050: Preclinical characterization of PRO1106, a novel and promising SLITRK6-directed sesutecan ADC

Abstract SLITRK6 is a type I transmembrane member of the SLITRK family of proteins and is highly expressed in certain epithelial tumors including urothelial, lung, breast cancer and glioblastoma, with minimal-to-low expression in normal tissues. Recent studies with a vedotin-based SLITRK6-directed ADC, AGS15E, have offered clinical proof-of-concept of harnessing this target with the ADC modality for addressing high unmet need at least in bladder cancer. PRO1106 is comprised of a proprietary humanized SLITRK6-targeting IgG1 (dubbed as “mAb”) and the proprietary topoisomerase 1 inhibitor-based linker-drug, sesutecan. Sesutecan previously demonstrated promising characteristics in preclinical studies with multiple targets and conferred an encouraging benefit:risk profile in the clinic with a FRα-directed ADC (rinatabart sesutecan). PRO1106 and the parent mAb exhibited strong binding (with low nanomolar affinity) to recombinant human or cynomolgus monkey SLITRK6 on bio-layer interferometry. No binding was observed with human SLITRK1 or SLITRK4 or in additional negative-binding assays. Potent cellular binding (with sub-nanomolar EC50) was also observed for the parent mAb and ADC with bladder, head and neck, and brain cancer cell lines as well as SLITRK6-overexpressing 293F cells. Target-binding was superior to sirtratumab (the parent antibody in AGS15E) and the binding epitope appeared to be distinct from that of sirtratumab in cross-block studies. PRO1106 displayed rapid internalization and elicited robust cytotoxicity (IC50 in the sub-nanomolar to low nanomolar range) in SLITRK6-expressing tumor cells but not target-negative cells. PRO1106 produced strong tumor growth inhibition in multiple cell-derived xenograft (CDX) models in mice representing bladder cancer and esophageal squamous cell carcinoma. PRO1106 showed a stable PK with much higher exposure compared to an in-house synthesized analog of AGS15E in rats. In an exploratory PK study in cynomolgus monkeys, PRO1106 at 5 mg/kg exhibited extended PK with minimal release of exatecan in circulation and with no apparent toxicity observed. In summary, PRO1106 is an ADC built on a clinically validated linker-drug directed at a clinically validated target, with promising data in preclinical pharmacology studies. As SLITRK6 expression in skin is negligible, PRO1106 may offer an exciting new option for patients with bladder cancer where the current standard-of-care ADC therapy (enfortumab vedotin) confers significant skin-related toxicity burden as well as for patients with additional cancer types. Citation Format: Wanwan Shen, Haotian Lu, Yang Xiao, Xuan Qiu, Haidong Liu, Lei Wang, Zhu Chen. Preclinical characterization of PRO1106, a novel and promising SLITRK6-directed sesutecan ADC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2050.

Abstract 6706: An anti-claudin 18.2/CD3 bispecific antibody for the treatment of claudin 18.2 positive gastric cancer

Abstract The claudin18.2 (CLDN18.2) protein shows four transmembrane domains (TMDs) with two extracellular loops (ECL), ECL-1 and ECL-2. It is a highly selective biomarker with limited expression in normal tissues and often exhibits abnormal expression during the occurrence and development of various primary malignant tumors. The specific expression pattern supports the notion that CLDN18.2 is a distinctive molecule for targeted therapy in various cancers, particularly gastric and pancreatic cancers. Various drugs targeting CLDN18.2, including monoclonal antibodies, ADCs, CAR-T, and bispecific antibodies, have also entered clinical trials. As of this writing, there are currently no commercially available products worldwide that specifically target CLDN18.2. However, Zolbetuximab (IMAB362) has successfully reached the Phase III end point, indicating positive clinical outcomes and establishing CLDN18.2 as a promising cellular and antibody therapeutic option. Here, we describe LNF2007, an anti-CLDN 18.2/CD3 bispecific antibody that can redirect CD3+ effector T cells to CLDN18.2+ tumor sites, resulting in the activation of T cells and subsequent killing of target cells. The design of LNF2007 focuses on selecting a relatively weak and reasonable affinity to CD3, accompanied by the suppression of Fc-mediated effector functions. This aim is to minimize off-target toxicity and maximize therapeutic efficacy. In vitro data demonstrate that LNF2007 binds more strongly to CLDN18.2+cells than to CD3+ cells. LNF2007 exhibited good dose-dependent activation and cytotoxicity against engineered cell lines BXPC3-hCLDN18.2-Luc and CHOK1-hCLDN18.2-Luc, which are positive for CLDN18.2 expression .In the in vivo pharmacodynamics assay, LNF2007 also demonstrated superior efficacy in the humanized NUGC4-CLDN18.2 model and BxPC3-CLDN18.2 model. Furthermore, a 4-week repeated dose (up to 1 mg/kg) toxicity study in cynomolgus monkeys showed that LNF2007 was safe and well tolerated. In vitro cytokine release was lower in the LNF2007 group than that in the AMG 910 and AZD5863 (two another anti-claudin18.2/CD3 bispecific antibody) groups. In conclusion, the novel anti-CLDN18.2 × anti-CD3 bispecific antibody LNF2007 demonstrates similar efficacy to AMG 910 and AZD5863 and is safer. LNF2007 provides a promising therapy for claudin 18.2-positive cancer patients.Taishan Industry Leading Talents Project of Shandong Province was a sponsor of this research. Citation Format: Lili Zhao, Guimin Zhang, Zhong Liu, Jinhua Xu, Lizhi Zhao, Guangyan Li, Bin Li, Zhongsong Zhu, Wei Peng, Yuqiang Zhu, Zhaowei Chen, Zhenyu Li. An anti-claudin 18.2/CD3 bispecific antibody for the treatment of claudin 18.2 positive gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6706.

Abstract 7179: OBI-992, a novel TROP2 targeting antibody drug conjugate demonstrates superior in vivo PK/PD properties and a favorable safety profile

Abstract Background: TROP2 targeting antibody-drug conjugates (ADC) have demonstrated promising clinical responses for the treatment of various solid tumors. However, these ADCs still exhibit serious safety issues, such as hematologic toxicities and interstitial lung disease. OBI-992, a novel TROP2 targeting ADC, which is derived from the conjugation of an anti-TROP2 antibody with a topoisomerase I inhibitor, exatecan, via an enzyme-cleavable linker. OBI-992 is designed to have high serum stability and broad therapeutic index. Herein, we describe the results from preclinical studies of OBI-992, including in vitro and in vivo stability, pharmacokinetics/pharmacodynamics (PK/PD) profile, and safety evaluation. Material and Methods: To characterize OBI-992, the linker stability was evaluated by ex vivo serum stability and rat PK studies. PK/PD properties, including systemic and tumor exposures as well as receptor occupancy, were evaluated in a human lung cancer xenograft model. In vitro toxicity testing, including ADC toxicity on differentiating neutrophils and FcγR mediated toxicity, was evaluated using human monocyte THP-1 cells. A 6-week repeat dose toxicity study in cynomolgus monkeys was conducted to evaluate the safety and toxicokinetics of OBI-992. Results: Ex vivo serum stability demonstrated that OBI-992 exhibited better linker stability than the benchmark datopotamab deruxtecan (Dato-DXd). In vivo PK evaluation in rats showed that OBI-992 had lower Cmax and AUC of free payload than Dato-DXd, indicating a better PK profile of OBI-992 in rats. A PK/PD study in tumor-bearing mice revealed that OBI-992 exhibited higher tumor exposure of free payload than Dato-DXd, resulting in a better antitumor efficacy. In addition, the antitumor effect positively correlated with percentage of receptor occupancy in a dose-dependent manner. In vitro cytotoxicity testing demonstrated that OBI-992 had lower toxicity in differentiating neutrophils and THP-1 cells compared to Dato-DXd, suggesting that OBI-992 may cause less off-target toxicity. Toxicokinetics of OBI-992 in cynomolgus monkeys revealed that the systemic exposure of ADC was similar to that of total antibody. Furthermore, the systemic exposure of ADC and total antibody were found to increase in a dose-proportional manner. Major toxicities in monkeys were target-related skin lesions. The highest non-severely toxic dose (HNSTD) was determined to be 60 mg/kg. Conclusions: OBI-992 exhibits remarkable antitumor efficacy and a favorable safety profile, supporting further clinical development of OBI-992 in TROP2 positive cancers. Citation Format: Chi-Sheng Shia, Shih-Ni Wen, Ren-Yu Hsu, Jyy-Shiuan Tu, Hui-Wen Chang, Wan-Fen Li, Ming-Tain Lai. OBI-992, a novel TROP2 targeting antibody drug conjugate demonstrates superior in vivo PK/PD properties and a favorable safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7179.

Abstract 2371: BGB-B167, a first-in-class 4-1BB/CEACAM5 bispecific antibody, exhibits potent in vitro and < for vivo antitumor activity and < for superior safety profile in preclinical models

Abstract 4-1BB (CD137) is a key costimulatory immunoreceptor and a promising therapeutic target in cancer. CEACAM5 (CEA) is a well-established tumor associated antigen overexpressed in many cancers, including colorectal, gastric, lung, pancreatic cancer, liver, breast and thyroid cancers. BGB-B167 is a novel immunoglobulin G (IgG)-based bispecific antibody targeting 4-1BB and CEA and is under clinical development for the treatment of advanced or metastatic solid tumors in humans. BGB-B167 binds to its target proteins with high specificity and affinity. Potent and CEA-dependent functional activities were demonstrated using peripheral blood mononuclear cell (PBMC)-based immune cell activation and cytotoxicity assays. In humanized 4-1BB knock-in mice bearing human CEA-expressing tumors, BGB-B167 exhibited potent, dose-associated single-agent efficacy as well as synergistic antitumor activity in combination with anti-PD-1 antibody. BGB-B167 was well tolerated in 1-month repeat-dose toxicology study in cynomolgus monkeys. Here, we describe the characterization of BGB-B167 with regard to preclinical proof-of-concept and basic drug-like properties. The combined dataset provides an overview on the design, mode of action, preclinical pharmacology and safety profile of BGB-B167. Citation Format: Zhuo Li, Liang Qu, Xin Chen, Liu Xue, Jie Li, Qi Liu, Jian Sun, Hanzi Sun, Yun Chen, Yuanyuan Xie, Wanyi Wang, Lin Zhu, Penghao Wang, Xiaosui Zhou, Hongjia Hou, Jie Chen, Xinyi Liu, Yilu Zhang, Ning Liu, Xinyi Liang, Shuo Zhang, Xiaoyan Tang, Jing Song, Tong Zhang, Xiaomin Song, Xuesong Liu, Kang Li, Chichi Huang. BGB-B167, a first-in-class 4-1BB/CEACAM5 bispecific antibody, exhibits potent in vitro and < for vivo antitumor activity and < for superior safety profile in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2371.

Abstract 6580: A Novel EGFR x cMET bispecific ADC PRO1286 demonstrated broad antitumor activity and promising tolerability in preclinical models

Abstract EGFR and cMET are frequently co-expressed on tumor cells, often upregulated as the escape mechanism for each other, and both well-validated targets in oncology. Small molecule TKIs and amivantamab have been approved for non-small cell lung cancer with relevant actionable genomic alterations (AGA), and monoclonal antibodies offer treatment options for EGFR-expressing head and neck and colorectal cancers without AGA. Yet high unmet need in these tumors still exists. We sought to develop an EGFR and cMET dual-targeting ADC using our proprietary technology platform with carefully chosen design features for the many tumors expressing EGFR and cMET with or without AGA. PRO1286 is comprised of a monovalent bispecific human IgG1 (dubbed as “Bsab”) with fine-tuned affinity on EGFR and cMET, and the proprietary topoisomerase 1 inhibitor-based linker-drug, sesutecan. Sesutecan previously demonstrated promising characteristics in preclinical studies with multiple targets and conferred an encouraging benefit:risk profile in the clinic with a FRα-directed ADC (rinatabart sesutecan). PRO1286 at DAR8 displays high hydrophilicity and excellent stability and developability in vitro. PRO1286 binds selectively and specifically to each target with a low nanomolar EC50 in the CHO-K1 cells overexpressing each target. PRO1286 exhibited efficient internalization (~50-80% internalized in 4 hrs) and strong cytotoxicity (sub-nanomolar IC50) against a broad panel of tumor cell lines with higher potency than the parent mAbs. PRO1286 produced marked and dose dependent anti-tumor activity in mouse xenograft models encompassing a wide range of target expression levels, tumor types (head and neck, lung, esophageal, gastric, colorectal), and genomic landscape (with or without AGA in EGFR or cMET; with diverse additional co-mutations). Sustained tumor growth inhibition or complete remission was observed in several xenograft models after treatment with a single dose (2 mg/kg) of PRO1286. PRO1286 was more efficacious than benchmarking molecules in the mouse studies. In an exploratory toxicity study in cynomolgus monkeys, PRO1286 was well tolerated at 30 mg/kg with the main toxicity being payload-driven and residing in bone marrow. PRO1286 exhibited a stable PK profile that was similar to that of the Bsab in rats and favorable PK characteristics in monkeys. In summary, PRO1286 demonstrated promising physiochemical properties, PK/PD, antitumor activity, and tolerability in preclinical studies. It may carry an expanded therapeutic index compared to other EGFR- and/or cMET-directed ADCs. It may also differentiate from existing EGFR- and/or cMET-targeting agents on broad coverage of EGFR and cMET-expressing tumors with or without the respective AGAs. Effort is under way to advance a DAR optimized molecule to the clinic for the treatment of many EGFR- or cMET-expressing solid tumors. Citation Format: Yang Xiao, Haiyu Huang, Jianhe Yin, Xuan Qiu, Lei Wang, Haidong Liu, Baiteng Zhao, Zhu Chen. A Novel EGFR x cMET bispecific ADC PRO1286 demonstrated broad antitumor activity and promising tolerability in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6580.

Abstract 739: AMT-253, a first-in-class MUC18-targeting antibody-drug conjugate, for the treatment of MUC18-positive solid tumors

Abstract MUC18, also known as MCAM (melanoma cell adhesion molecule) or CD146, is a type I transmembrane glycoprotein originally identified as a cell adhesion molecule of melanoma that plays important roles in tumor growth and progression including tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis. MUC18 is overexpressed in a variety of solid tumors including (but not limited to) melanoma, osteosarcoma, head and neck, lung, esophagus, breast, ovarian, and cervical cancer and hepatocellular carcinoma, with restricted presence on normal healthy tissues, mainly on blood vessels and a minor subset of T helper cells. Limited expression in normal tissues and high expression in tumors makes MUC18 a promising target for the development of antibody drug conjugate (ADC). AMT-253 is a novel ADC targeting MUC18. It is composed of a humanized MUC18-targeting IgG1 antibody conjugated with Exatecan, a topoisomerase I inhibitor, attached to a proprietary self immolative T moiety linker through reduced interchain disulfide bonds with a drug-to-antibody ratio (DAR) of 8. AMT-253 was stable in vitro with less than 0.5% of payload releasing when incubated with human, monkey, mouse or rat plasma for 21 days at 37°C. AMT-253 selectively bound to cell surface MUC18 and was efficiently internalized into MUC18-positive cancer cells. AMT-253 exhibited antiproliferative activity against several MUC18-positive cancer cell lines and demonstrated potent bystander killing effect in vitro. Treatment with AMT-253 resulted in tumor growth inhibition or regression in a panel of MUC18 positive cell line derived xenograft (CDX) or patient derived xenograft (PDX) models. In addition, AMT-253 was well tolerated in a GLP compliant toxicity study in cynomolgus monkeys at dose levels ≤45 mg/kg. Taken together, our preclinical in vivo efficacy and toxicity studies demonstrated that AMT-253 has a wide therapeutic window and could potentially provide benefits for cancer patients with highly unmet medical needs. AMT-253 is currently being evaluated in a Phase I first-in-human clinical trial (NCT05906862). Citation Format: Jing Shi, Jiaqing Yan, Yaling Huang, Jun Guo, Yan Kong, Xun Meng, Shu-Hui Liu. AMT-253, a first-in-class MUC18-targeting antibody-drug conjugate, for the treatment of MUC18-positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 739.

Abstract 1812: Development of novel topoisomerase 1 inhibitor PBX-7 payload-based ADC including tandem cleavable linker system

Abstract Antibody-Drug Conjugates (ADC) employing camptothecin-based payloads are gaining high interests as a new modality to treat various cancers, especially solid tumors. Among them, novel ADCs containing synthetic camptothecin-based payloads specially optimized for ADC applications (e.g., DXd) are of special interest due to their successful clinical results. Despite the remarkable success of ADCs exploiting these payloads, such as Enhertu (DS-8201a), there are still clear unmet needs, including the improvement of safety profile (minimization of ILD and neutropenia) and the development of novel ADCs with multiple MoA payloads to combat cancer heterogeneity. To address these unmet needs, we have synthesized and evaluated a series of PBX-7 payloads, derived from novel camptothecin FL118, a potent, dual inhibitor of Top 1/anti-apoptotic pathway known for its favorable safety profile. These compounds showed strong in vitro cytotoxicity across various cancer cell lines and inhibition of Top 1 comparable to DXd or other related camptothecin compounds. They had excellent safety profile in the preliminary toxicity study in mice that can be attributed to their physicochemical properties. PBX-7 series payloads based ADC exhibited superior cellular cytotoxicity and in vivo tumor regression compared to Enhertu in Her2-positive cell line and CDX mouse model. Notably, PBX-7 based ADC demonstrated remarkable efficacy in reducing tumor volume more than Enhertu in the T-DM1-resistant JIMT-1 xenograft mouse model. Furthermore, PBX-7 based ADC have bystander effects similar to Enhertu, leading to reduced viability of antigen-negative cells when co-cultured with antigen-positive cell lines. In NHP toxicity study in Cynomolgus monkeys, no sign of toxicity was observed when dosed with Trastuzumab-PBX-7016 up to 30mg/kg. As another way of addressing unmet needs, we synthesized novel linker including tandem cleavage site to reduce payload mediated toxicity. Two distinct enzyme, beta-glucuronidase and cathepsin B cleave linker sequentially. This linker system has a higher stability during circulation in the body and higher specific payload release in the tumor tissue than single cleavable linker. In conclusion, our research shows the promising potential of novel camptothecin PBX-7 based ADCs and tandem cleavable linker system as potent and safe ADC candidates for cancer therapy. These advancements hold great promise in addressing the current challenges in ADC development with their enhanced safety profiles and targeted efficacy. Citation Format: Younghwa Chun, Areum Go, Hyun Yong Cho, Byeong Sung Lee, Seunggun Shin, JaeHyeon Lee, Sohui Kweon, Hyemin Han, Suhyun Park, Doo Young Jung. Development of novel topoisomerase 1 inhibitor PBX-7 payload-based ADC including tandem cleavable linker system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1812.

Abstract 4080: IBB0979, A novel B7H3/IL-10 immunocytokine of monovalent anti-B7H3 antibody fused with IL-10 homodimer

Abstract Background: This study demonstrates the preclinical evaluation of a novel B7H3/IL-10 immunocytokine IBB0979. IBB0979 was designed to solve the problems of immune cell exhaustion and drug resistance in current immunotherapy. As the tumors progress, the domination of progenitor exhausted T cells (which are the major target cells of current PD-1/L1 based immunotherapy) will be replaced by terminally exhausted T cells (which are the major target cells of IL-10) causing resistance of current PD-1/L1 based therapies. Thus, IL-10 is a potent activator of antigen-specific CD8+ T cells in the tumor microenvironment and can restore the tumor-killing activity of tumor-infiltrating lymphocytes by restoring the oxidative phosphorylation metabolism of terminally exhausted T cells. B7H3 is highly expressed on various tumors but expressed at lower levels in normal tissues and blood vessels, which makes it an ideal target for developing cancer treatment. Also, B7H3 antibody extended the half-life and performed tumor-targeted delivery of IL-10, which improves the safety and efficacy of IL-10. Methods: We designed several structures of B7H3 antibody and IL-10 bifunctional fusion protein. Binding activity to B7H3 and IL-10 receptor was evaluated by both ELISA and FACS. C57BL/6J mice bearing MC38-hB7H3 cell line were used to evaluate the anti-tumor efficacy of IBB0979. Preclinical PK and toxicity study was also performed in cynomolgus monkeys to describe the safety profile of IBB0979. Results: Preclinical study showed that IBB0979 has high affinity to both targets and exhibited potent TGI in C57BL/6J mice bearing MC38-hB7H3 cell line, with TGI of 100% at 0.3mg/kg, 1mg/kg and 3mg/kg. An in vivo study in cynomolgus monkeys showed that after intravenously administered with 1 mg/kg, 2 mg/kg and 6 mg/kg of IBB0979 once a week for 29 days (5 times in total, given on days 1, 8, 15, 22 and 29), MTD was not reached up to 6 mg/kg which is significantly higher than the 10-20 μg/kg tolerated by IL-10 cytokines alone. Conclusion: IBB0979 is the world's first B7H3/IL-10 immunocytokine receiving IND approvals from both the FDA and the NMPA, showing excellent preclinical efficacy and safety profile. The Phase I clinical trial is currently on-going, with the first patient dosed in July 2023 and achieved SD at first efficacy evaluation after 2 cycles of administration. Since B7H3 is overexpressed in a wide range of cancers including lung, prostate, glioma, thyroid, head and neck, rectal, breast, skin, renal cell, and ovarian cancers, IBB0979 has the potential to become a next-generation therapy for resolving T cell exhaustion in cancer patients. Citation Format: Xiaoling Jiang, Chongbing Wu, Zi Chen, Liusong Yin. IBB0979, A novel B7H3/IL-10 immunocytokine of monovalent anti-B7H3 antibody fused with IL-10 homodimer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4080.