An affinity threshold for maximum efficacy in anti-PD-1 immunotherapy

Cowles, Sarah C.; Sheen, Allison; Santollani, Luciano; Lutz, Emi A.; Lax, Brianna M.; Palmeri, Joseph R.; Freeman, Gordon J.; Wittrup, K. Dane

doi:10.1080/19420862.2022.2088454

Cited by 7 publications

(4 citation statements)

References 60 publications

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“…30 Cowles et al elucidated that higher affinity correlated with increased target saturation in the case of anti-PD-1 antibodies. 31 The K D value of the reported PD-L1 tracers ranges from 328.0 to 2.0 nM. We assumed that high or ultra-high affinity tracers can rapidly detect PD-L1 expressed at low abundance.…”

Section: Discussionmentioning

confidence: 99%

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Zhang,

Cao,

et al. 2024

J Immunother Cancer

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BackgroundThe programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells’ immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors’ immunotherapy landscape.MethodsBy immunizing an alpaca with recombinant human PD-L1, three clones of thevariable domain of theheavy chain ofheavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC).ResultsWhile RW102 has a high binding affinity to PD-L1 with an excellent KDvalue of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KDvalue of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have differentin vivocirculation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies.ConclusionsWe developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments.Trial registration numberNCT06165874.

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Section: Discussionmentioning

confidence: 99%

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Zhang,

Cao,

et al. 2024

J Immunother Cancer

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“…Finally, although OX108 has a relatively low affinity (K D = 84 nM), it is a well-documented CD200R-blocking antibody [ 24 ], and we were able to confirm successful tumour penetration and binding via a reduction of CD200R MFI on TIICs. Nevertheless, higher-affinity monoclonal antibodies targeting CD200R should also be tested, as affinity is claimed to correlate with efficacy [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Combination CD200R/PD-1 blockade in a humanised mouse model

Fellermeyer

Anzilotti

Paluch

et al. 2023

Immunotherapy Advances

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There is an increasing number of immune-checkpoint inhibitors being developed and approved for cancer immunotherapy. Most of the new therapies aim to reactivate tumour-infiltrating T cells, which are responsible for the tumour killing. However, in many tumours, the most abundant infiltrating immune cells are macrophages and myeloid cells, which can be tumour-promoting as well as tumouricidal. CD200R was initially identified as a myeloid-restricted, inhibitory immune receptor, but was subsequently also found to be expressed within the lymphoid lineage. Using a mouse model humanised for CD200R and PD-1, we investigated the potential of a combination therapy comprising Nivolumab, a clinically approved PD-1 blocking antibody, and OX108, a CD200R antagonist. We produced Nivolumab as a murine IgG1 antibody and validated its binding activity in vitro as well as ex vivo. We then tested the combination therapy in the immunogenic colorectal cancer model MC38 as well as the PD-1 blockade-resistant lung cancer model LLC1, which is characterised by a large number of infiltrating myeloid cells, making it an attractive target for CD200R blockade. No significant improvement of overall survival was found in either model, compared to Nivolumab mIgG1 monotherapy. There was a trend for more complete responses in the MC38 model, but investigation of the infiltrating immune cells failed to account for this. Importantly, MC38 cells expressed low levels of CD200, whereas LLC1 cells were CD200-negative. Further investigation of CD200R blocking antibodies in tumours expressing high levels of CD200 could be warranted.

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“…Fam20C kinase with a KDEL tag ( 22 ) and MSA-IL2 with a 6-His tag ( 47 ) were previously cloned into the gWiz vector. αPD1 was cloned into the gWiz vector starting with the sequence of 29F.1A12, which was a generous gift from the G. Freeman Laboratory (Dana-Farber Cancer Institute, Boston, MA) ( 79 , 80 ). This clone is typically used in the rat IgG2a format, but we cloned it with a murine IgG2c isotype with a kappa light chain and the LALA-PG mutations to ablate Fc effector functions and prevent target cell clearance ( 81 ).…”

Section: Methodsmentioning

confidence: 99%

Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies

Lutz

Agarwal

Momin

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFNα and IFNβ therapies have proven promising in humans, but suffer from limited efficacy and high toxicity. Intratumoral IFN retention ameliorates systemic toxicity, but given the complexity of IFN signaling, it was unclear whether long-term intratumoral retention of type I IFNs would promote or inhibit antitumor responses. To this end, we compared the efficacy of IFNα and IFNβ that exhibit either brief or sustained retention after intratumoral injection in syngeneic mouse tumor models. Significant enhancement in tumor retention, mediated by anchoring these IFNs to coinjected aluminum-hydroxide (alum) particles, greatly improved both their tolerability and efficacy. The improved efficacy of alum-anchored IFNs could be attributed to sustained pleiotropic effects on tumor cells, immune cells, and nonhematopoietic cells. Alum-anchored IFNs achieved high cure rates of B16F10 tumors upon combination with either anti-PD-1 antibody or interleukin-2. Interestingly however, these alternative combination immunotherapies yielded disparate T cell phenotypes and differential resistance to tumor rechallenge, highlighting important distinctions in adaptive memory formation for combinations of type I IFNs with other immunotherapies.

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An affinity threshold for maximum efficacy in anti-PD-1 immunotherapy

Cited by 7 publications

References 60 publications

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Combination CD200R/PD-1 blockade in a humanised mouse model

Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies

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An affinity threshold for maximum efficacy in anti-PD-1 immunotherapy

Cited by 7 publications

References 60 publications

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers

Combination CD200R/PD-1 blockade in a humanised mouse model

Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies

Contact Info

Product

Resources

About

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers