Clinical Experiences With Anti-CD137 and Anti-PD1 Therapeutic Antibodies

doi:10.1053/j.seminoncol.2010.09.008

Seminars in Oncology

Volume 37, Issue 5, October 2010, Pages 508-516

https://doi.org/10.1053/j.seminoncol.2010.09.008 Get rights and content

Monoclonal antibodies (mAbs) provide a pharmacological platform to block or activate the function of surface receptors. The immune system has evolved receptor–ligand pairs that repress or empower the cellular immune response, which, if tampered with, unleash more potent cellular immunity against tumor antigens. Agonist antibodies directed against CD137 (4-1BB) on the surface of antigen-primed T lymphocytes increase tumor immunity that is curative against some transplantable murine tumors. A fully human IgG4 anti-CD137 antibody is under development with signs of clinical activity and cases of severe liver toxicity that seem to be on-target and dose-dependent effects. Programmed death-1 (PD1) is a surface molecule delivering inhibitory signals important to maintain T-cell functional silence against their cognate antigens. Interference with PD1 or its ligand PD-L1 (B7-H1) increases antitumor immunity. As a result anti-PD1 and anti–PD-L1 human mAbs are under clinical development. Phase I trials with anti-PD1 mAb have yielded encouraging results with durable objective responses and a reasonable safety profile. As new class of drugs in cancer therapy, immunostimulatory mAbs have resulted in redefinition of tumor response criteria and rethinking of the rationale for combining these among each other and with other strategies.

Section snippets

Anti-CD137 Antibody

CD137 (4-1BB) is an inducible T-cell surface molecule that belongs to the tumor necrosis factor (TNF) receptor superfamily. Its binding by the natural ligand (CD137L) or by an agonist antibody provides costimulation in a CD28-independent pathway for CD4⁺ and CD8⁺ T cells.4, 5 Surface expression of CD137 is detectable on activated effector CD8⁺ and CD4⁺ T cells, and also on activated natural killer (NK) cells, NK/T cells, regulatory T cells (Tregs), dendritic cells (DCs), macrophages,

Anti-CD137 Antibodies: Preclinical Data

Most studies focused on two anti-CD137 mAb: BMS 469492 that is an anti-murine CD137 mAb, and BMS 663513 that is a fully human IgG4 mAb against human CD137. BMS 469492 was used for studies in murine tumor models, and it does not cross-react with BMS 663513. Both are agonistic mAbs and do not block the interaction of CD137 with its natural ligand, CD137L. It is of note that mAbs that do block CD137L binding show similar functional antitumor activities when compared to nonblocking mAbs. BMS 663513

Anti-CD137 Toxicology

Several studies with BMS 469492 in mice and with BMS 663513 in monkeys showed a good tolerability of these two mAbs in vivo. The administration of BMS 469492 at doses of 10 or 50 mg/kg twice weekly for 4 weeks to CD-1 mice resulted in skin and liver toxicity. Skin toxicity consisted of alopecia, scabbing, and scaly areas; liver toxicity was characterized by elevation of AST and ALT with local inflammation and increased mRNA expression of CD137, IFN-γ, and IL-12. These toxicities were time- but

Clinical Studies With Anti-CD137 Antibodies

Table 1 summarizes the clinical studies using anti-CD137 mAb as an anticancer agent.

The NCT00309023 study was an open-label, ascending, multi-dose phase I-II study conducted in subjects with locally advanced or metastatic solid tumors.²⁹ In the dose-escalation phase of the study, subjects were sequentially assigned to one of six dose-cohorts (0.3, 1, 3, 6, 10, or 15 mg/kg) to receive BMS 663513 as a 60-minute intravenous (IV) infusion once every 3 weeks. In the dose-expansion portion of the

Anti-PD1 Antibody

PD1 (CD279) is an inhibitory co-receptor expressed on antigen-activated T cells, on antigen-specific T cells that are chronically exposed to antigen, and on B cells. It belongs to the CD28 family and has two known ligands: B7-H1/PD-L1 (hereafter B7-H1), the predominant mediator of PD1–dependent immunosuppression, and B7-DC/PD-L2. PD-L1 is expressed on hematopoietic cells and can be upregulated upon their activation. PD-L1 is also found in tissues such as pancreatic islets, heart, endothelium,

Anti-PD1 Antibodies: Preclinical Data

Some preclinical studies focused on the combination of cellular immunotherapy and anti-PD1 mAb. A murine anti-PD1 mAb (4H2) was developed to study its effect on murine ligands. This antibody showed ability to inhibit the interaction between mouse PD1 and its ligand PD-L1 or PD-L.³⁷ The variable (V) region sequences of this antibody were determined, and VH and VK sequences were grafted into the murine IgG1Fc region and the murine Cn constant region, respectively, to generate an antibody with

Anti-PD1 Toxicology and Clinical Studies

At present only phase I trials that have evaluated anti-PD1 in solid tumors as phase II studies are still under evaluation. Table 2 summarizes the current studies with anti-PD1 mAbs as anticancer agents.

A phase I clinical trial of PD1 blockade with the fully human mAb MDX-1106 (BMS 936558/ONO-538, IgG4) specific for human PD1 was conducted in 39 patients with advanced treatment-refractory solid tumors such as non-small cell lung cancer (NSCLC), hormone-refractory prostate cancer (HRPC),

Conclusion

Targeted tumor immunotherapy is an exciting field, although in many aspects it will challenge our common wisdom regarding drug development in oncology. The cellular immune response is tightly modulated to control the ability to generate cytotoxicity and inflammation and we are just starting to learn how to unleash or stimulate it within a reasonably safe therapeutic window. Understanding its control offers an opportunity to regulate its intensity. CD137 and PD1 certainly stand out as promising

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: Disclosure of Potential Conflicts of Interest: P.A.A. participated in advisory boards from Bristol Myers Squibb and GSK; he receives honoraria from Bristol Myers Squibb and Schering Plough. I.M. has received consultancy honoraria and recombinant proteins from Bristol Myers Squibb and Pfizer Inc.

View full text

Immunologic checkpoints for cancer treatment: From scientific rationale to clinical applicationClinical Experiences With Anti-CD137 and Anti-PD1 Therapeutic Antibodies

Section snippets

Anti-CD137 Antibody

Anti-CD137 Antibodies: Preclinical Data

Anti-CD137 Toxicology

Clinical Studies With Anti-CD137 Antibodies

Anti-PD1 Antibody

Anti-PD1 Antibodies: Preclinical Data

Anti-PD1 Toxicology and Clinical Studies

Conclusion

Trends Pharmacol Sci

Blood

Blood

Clin Genitourin Cancer

Neoplasia

CTLA-4: new insights into its biological function and use in tumor immunotherapy

Nat Immunol

Improved survival with ipilimumab in patients with metastatic melanoma

N Engl J Med

Immunostimulatory monoclonal antibodies for cancer therapy

Nat Rev Cancer

Involvement of tumor necrosis factor receptor superfamily (TNFRSF) members in the pathogenesis of inflammatory diseases

Exp Mol Med

TNF/TNFR family members in costimulation of T cell responses

Annu Rev Immunol

CD137 expression in tumor vessel walls: high correlation with malignant tumors

Am J Clin Pathol

4-1BB promotes the survival of CD8-T lymphocytes by increasing expression of Bcl-xL and Bfl-1

J Immunol

Costimulation of human CD28- T cells by 4-1BB ligand

Eur J Immunol

In vivo depletion of DC impairs the anti-tumor effect of agonistic anti-CD137 mAb

Eur J Immunol

Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors

J Clin Invest

Evaluating the cellular targets of anti-4-1BB agonist antibody during immunotherapy of a pre-established tumor in mice

PLoS One

Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease

Nat Med

CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice

J Clin Invest

Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time dependent

J Clin Invest

Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity

Cancer Res

Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ

Cancer Immunol Immunother

Assessment of tissue biomarkers following anti-CD137 treatment in the EMT-6 mouse tumor model

Proc Am Assoc Cancer Res (Meeting Abstracts)

Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines

Cancer Res

Immunologic checkpoints for cancer treatment: From scientific rationale to clinical application
Clinical Experiences With Anti-CD137 and Anti-PD1 Therapeutic Antibodies