Dataset Information

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.

ABSTRACT:

Purpose

CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease.

Experimental design

We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques.

Results

CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration.

Conclusions

CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.

SUBMITTER: Archer S

PROVIDER: S-EPMC11016891 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Publications

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.

Archer Sophie S Brailey Phillip M PM Song Minjung M Bartlett Phillip D PD Figueiredo Ines I Gurel Bora B Guo Christina C Brucklacher-Waldert Verena V Thompson H Lorraine HL Akinwale Jude J Boyle Samantha E SE Rossant Christine C Birkett Neil R NR Pizzey Julia J Maginn Mark M Legg James J Williams Richard R Johnston Colette M CM Bland-Ward Philip P de Bono Johann S JS Pierce Andrew J AJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20240401 8

<h4>Purpose</h4>CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this imm ...[more]

PMID: 38593226

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Project description:PurposeThe present study aims at developing and evaluating an urea-based prostate specific membrane antigen (PSMA) inhibitor suitable for labeling with 111In for SPECT and intraoperative applications as well as 68Ga and 64Cu for PET imaging.MethodsThe PSMA-based inhibitor-lysine-urea-glutamate-coupled to the spacer Phe-Phe-D-Lys(suberoyl) and functionalized with the enantiomerically pure prochelator (R)-1-(1-carboxy-3-carbotertbutoxypropyl)-4,7-carbotartbutoxymethyl)-1,4,7-triazacyclononane ((R)-NODAGA(tBu)3), to obtain (R)-NODAGA-Phe-Phe-D-Lys(suberoyl)-Lys-urea-Glu (CC34). CC34 was labeled with 111In, 68Ga and 64Cu. The radioconjugates were further evaluated in vitro and in vivo in LNCaP xenografts by biodistribution and PET studies. Biodistribution studies were also performed with 68Ga-HBED-CC-PSMA (HBED-CC: N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) and 111In-PSMA-617 for comparison.Results68Ga-CC34, 64Cu-CC34, and 111In-CC34 were prepared in radiochemical purity > 95%. 68/natGa-CC34, 64/natCu-CC34, 111/natIn-CC34, 68/natGa-HBED-CC-PSMA, and 111/natIn-PSMA-617 exhibited high affinity for the LNCaP cells, with Kd values of 19.3 ± 2.5 nM, 27.5 ± 2.7 nM, 5.5 ± 0.9 nM, 2.9 ± 0.6 nM and 5.4 ± 0.8 nM, respectively. They revealed comparable internalization profiles with approximately 75% of the total cell associated activity internalized after 3 h of incubation. 68Ga-CC34 showed very high stability after its administration in mice. Tumor uptake of 68Ga-CC34 (14.5 ± 2.9% IA/g) in LNCaP xenografts at 1 h p.i. was comparable to 68Ga-HBED-CC-PSMA (15.8 ± 1.4% IA/g) (P = 0.67). The tumor-to-normal tissue ratios at 1 and 2 h p.i of 68Ga-CC34 were also comparable to 68Ga-HBED-CC-PSMA (P > 0.05). Tumor uptake of 111In-CC34 (28.5 ± 2.6% IA/g) at 1 h p.i. was lower than 111In-PSMA-617 (52.1 ± 6.5% IA/g) (P = 0.02). The acquisition of PET-images with 64Cu-CC34 at later time points showed wash-out from the kidneys, while tumor uptake still remained relatively high. This resulted in an increased tumor-to-kidney ratio over time.Conclusions68Ga-CC34 is comparable to 68Ga-HBED-CC-PSMA in terms of tumor uptake and tumor to normal tissue ratios. 64Cu-CC34 could enable high contrast imaging of PSMA positive tissues characterized by elevated expression of PSMA or when delayed imaging is required. 64Cu-CC34 is currently being prepared for clinical translation.

Project description:PurposeParacrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters.Experimental designAnimals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction.ResultsMultiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect.ConclusionsThis dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.

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Dataset Information

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.

Purpose

Experimental design

Results

Conclusions

Publications

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.

Similar Datasets

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