What is the Immunotherapy targeting ADCC for HER2+ breast cancer?
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What is the Immunotherapy targeting ADCC for HER2+ breast cancer?
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What is the Immunotherapy targeting ADCC for HER2+ breast cancer?
In breast cancer ( BC ) patients, Her2 overexpression is found in 15–20% of tumors and is associated with more aggressive disease and worse prognosis.
Her2-targeted therapy significantly improves the prognosis of patients with Her2-positive breast cancer and gastric cancer.
Currently, several anti-Her2-targeted drugs have been approved for the treatment of breast cancer: trastuzumab and pertuzumab, both of which are anti-Her2 human monoclonal antibodies, combined with chemotherapy are approved as first-line treatment for metastatic breast cancer.
However, in the metastatic setting, patients may experience disease relapse after treatment.
In the current era of evolving immunotherapy drugs, the understanding of the immune response generated by anti-HER2 antibodies is advancing rapidly.
Trastuzumab treatment promoted the activation of natural killer ( NK ) cells in BC patients overexpressing HER2 , suggesting that the efficacy of Trastuzumab monotherapy, in addition to direct inhibition of Her2, may also be related to antibody-dependent cell-mediated cytotoxicity ( ADCC ).
Currently, dual Her2 blockade with trastuzumab and pertuzumab is the standard of care for both early and advanced Her2+ cancers because of the potential additive effect of this combination in ADCC.
However, in patients with relapsed or progressive disease, ADCC may be hindered by multiple factors, such as FcγRIIIa polymorphisms and the immunosuppressive microenvironment.
Therefore, new drug development strategies are being investigated to enhance the ADCC effect elicited by anti-HER2 therapy.
The mechanism of action of ADCC
ADCC is a cell-mediated immune response through which immune cells induce cell death when specific antibodies bind to the target cell membrane.
This is one of several mechanisms by which antibodies , a major aspect of the humoral immune response, limit and control infection.
Normally, the ADCC effect mainly activates NK cells through FCR-binding antibodies, and the most characteristic FcR on the NK cell membrane is FcγRIII ( CD16 ).
Once FcR binds to the Fc fragment of IgG, NK cells release different cytotoxic molecules, which trigger the death of target cells. FcyRs consist of three distinct classes: FcyRI ( CD64 ), FcyRII ( CD32 ) including FcRIIa and FcRIIb, and FcyRIII including FcRIIIa and FcRIIIb.
FcγRI is a high-affinity receptor that can bind to monomeric IgG, while FcγRII and FcγRIII have lower affinity for monomeric molecules and fully interact with multimeric immune complexes.
FCRIIb induces inhibitory signals in monocytes/macrophages and polymorphonuclear cells; in contrast, FcyRIIa and FcyRIIIa activate monocytes, macrophages, and NK cells.
While most immune cells co-express activating and inhibitory FcγRs, NK cells are special in that they only constitutively express activating, low-affinity FcγRIIIa.
Trastuzumab-mediated ADCC
As one of the main mechanisms of action of various monoclonal antibody therapeutic effects, ADCC has been validated in clinical patients.
It is currently known to be one of the main mechanisms of action of rituximab ( anti-CD20 ), cetuximab ( anti-EGFR ) and trastuzumab.
Along with the release of cytotoxic granules such as granzyme and perforin, NK cells release pro-inflammatory cytokines such as IFN-γ and TNF-α during ADCC, a mechanism known as antibody-dependent cytokine release ( ADCR ).
Trastuzumab treatment promoted NK cell activation in BC patients overexpressing Her2, suggesting that the efficacy of trastuzumab is related to the ADCC mechanism.
Anti-Her2 antibody-mediated interactions between NK cells and tumor cells, as well as ADCC-induced pro-inflammatory milieu, can modulate other immune cell populations to produce a “vaccine effect” via therapeutic antibodies.
Given that activation of Her2 signaling requires receptor homodimerization or heterodimerization with other members of the Her receptor family, a second anti-Her2 antibody, pertuzumab, was developed to prevent ligand-induced Her2 dimerization .
The combination of pertuzumab and trastuzumab expressed synergistic induction of tumor regression in a Her2+ BC xenograft model. In vitro evaluation of ADCC demonstrated that both trastuzumab and pertuzumab, applied as single agents, were effective in activating ADCC with equal potency.
In vivo studies showed that the combination of trastuzumab and pertuzumab increased NK cell migration into tumors and alleviated trastuzumab resistance in a BC xenograft model.
At subsaturating doses, the combination of the two drugs conferred an additive effect on ADCC compared with monotherapy.
Strategies and clinical progress of enhancing anti-Her2 ADCC
The activity of NK cells is known to be determined by the balance of signals generated by inhibitory and activating receptors on the cell surface.
Different strategies to enhance NK cell activation can be combined to enhance their ADCC effects.
Blocks inhibitory signals from NK cells
Monalizumab ( IPH2201 ) is an immune checkpoint inhibitor that targets the NKG2A receptor expressed on NK cells and tumor-infiltrating cytotoxic CD8+ T cells.
Monalizumab blocks the interaction between NKG2A and HLA-E, restoring the broad antitumor response mediated by these cells.
Therefore, it enhances the cytotoxic potential of other therapeutic antibodies.
Given the encouraging results of this antibody in combination with cetuximab, a Phase II clinical trial ( MIMOSA ) is evaluating the combination of monalizumab and trastuzumab in patients with metastatic or locally incurable HER2-positive BC.
Targeted NK cell activation
4-1BB ( CD137 ) is a costimulatory immune receptor, a member of the TNF receptor superfamily, mainly expressed on activated CD4+ and CD8+ T cells, activated B cells and NK cells.
Utomilumab is a fully humanized IgG2 monoclonal antibody that is an agonist antibody for 4-1BB.
A Phase I clinical trial ( NCT03364348 ) of utomilumab in combination with trastuzumab or trastuzumab emtansine in patients with HER2-positive BC is ongoing.
In addition, the AVIATOR study ( NCT03414658 ) is also evaluating trastuzumab in combination with Vinorelbine, Avelumab and Utomilumab in advanced HER2+ BC.
IL-2 is an immunostimulatory cytokine that enhances NK cell responses.
RO6874281 is a recombinant fusion protein composed of a human monoclonal antibody against fibroblast activation protein alpha ( FAP ) coupled to an engineered variant of IL-2 ( IL-2v ).
FAP is a cell surface protein expressed on a variety of cancer cells. Currently, the BP29842 study is evaluating the safety, tolerability and efficacy of RO6874281 in combination with trastuzumab in patients with Her2+ metastatic or recurrent BC.
IL-12 was originally named NK cell stimulating factor and is basically produced by APC cells such as DCs, monocytes and macrophages[. IFN-γ is the most potent mediator of IL-12 action in NK and T cells, stimulating the maturation and cytotoxicity of activated NK cells, CD8+ and CD4+ T cells, and enhancing ADCC against tumor cells.
In a phase I clinical trial of trastuzumab in combination with IL-12 in patients with HER2+ tumors, positive clinical outcomes were associated with IFN-γ production by NK cells.
Follow-up phase I trials of trastuzumab, IL-12, and paclitaxel confirmed these results.
Despite high expectations, clinical studies of IL-12 have not given sufficient results, probably due to the gradual decline in adaptive responses and IFN-γ induction following IL-12 injection.
IL-15 has a stimulatory function similar to IL-2 and is essential for the development and function of NK cells.
NKTR-255 is a polymer-conjugated human IL-15 designed to activate the IL-15 pathway, expand NK cells, and promote the survival and development of memory CD8+ T cells without Treg induction.
NKTR-255 enhances the tumor growth inhibitory activity of trastuzumab in a mouse human tumor xenograft model, and while no clinical trials have been performed on this compound, preclinical evidence suggests that it may promote tumor growth in HER2+ BC. application.
ALT-803 ( N803 ) is an IL-15 superantigen consisting of an IL-15 mutant ( N72D ) and an IgG1Fc fusion.
In a phase 1 clinical trial, the expansion of total lymphocytes and CD8+ T cells was limited with the drug, however, NK cell counts were significantly increased.
These data, along with compelling evidence of synergy in preclinical and clinical studies, provide a rationale for combining it with drugs already in clinical practice, such as the anti-HER2 antibody ± Avelumab .
Combined immune checkpoint inhibitor
Avelumab is a fully human IgG1 anti-PD-L1 mAb that retains the ability of its Fc portion to induce ADCC by binding to CD16.
A phase I JAVELINI trial targeting solid tumors using Avelumab as a single agent in heavily pretreated metastatic BC patients had a lower ORR of 3.0%.
However, responses were higher in patients with high PD-L1 expression ( ORR 16.7% vs 1.6% ) and were surprisingly prolonged in the TNBC subset of patients.
The AVIATOR study ( NCT03414658 ), currently evaluating trastuzumab plus vinorelbine in combination with Avelumab and utomilumab in combination with Avelumab, will provide more information on the role of Avelumab in advanced HER2+ BC.
Magrolimab is a humanized monoclonal antibody that blocks the interaction of CD47 with signal regulatory protein-α ( SIRPα ), thereby promoting macrophage-mediated phagocytosis.
A recent preclinical study showed that the combination of Magrolimab and trastuzumab eliminated HER2+ BC cells due to enhanced phagocytosis of Ab-dependent cells by macrophages.
FcγR affinity changes enhance ADCC
Margetuximab binds to the same HER2 epitope with trastuzumab with equal affinity and exhibits antiproliferative activity similar to trastuzumab in vitro.
Using an engineering technology platform, five amino acids were modified into the margetuximab IgG1 Fc domain.
These changes increased its binding to the activating isoform of FcγRIIIa and decreased its interaction with the inhibitory FcγRIIb.
In xenograft studies, Margetuximab showed enhanced anti-HER2-expressing tumor activity in transgenic mice bearing the human FcγRIIIa 158F ( low binding allele ).
Recently, results from an open-label Phase III trial of margetuximab were announced.
The SOPHIA trial ( NCT02492711 ) enrolled 538 patients with advanced HER2-positive metastatic BC and compared margetuximab plus chemotherapy with trastuzumab plus chemotherapy.
All patients had received trastuzumab and pertuzumab, and more than 90% had also received T-DM1.
Compared with trastuzumab, margetuximab improved PFS, with a median PFS of 5.8 months vs 4.9 months ( p=0.03 ). The ORR was higher with margetuximab: 25.2% vs 13.7%, the clinical benefit rate improved from 35.6% for trastuzumab to 48.1% for margetuximab ( p=0.0025 ), and the mean duration of response was similar in both groups.
In a planned exploratory analysis by FcRIII genotype, patients with the low-affinity FcγIIIa genotype harboring the 158F allele had increased benefit, with a 32% reduction in disease progression.
In the second interim analysis, among patients with the FcIIIa 158F allele ( 85% ), median OS was extended by 4.3 months in the margetuximab group to 23.7 months compared with 19.4 in the trastuzumab group month ( P=0.087 ). In addition, safety and discontinuation rates were comparable between the margetuximab and trastuzumab groups.
TrasGEX is a second-generation monoclonal antibody to trastuzumab that is carbohydrate-optimized to enhance ADCC while fully retaining the antigen-binding properties of trastuzumab to HER2.
TrasGEX was evaluated for safety, pharmacokinetics ( PK ) and preliminary antitumor activity in a Phase I dose escalation study ( NCT01409343 ).
The results showed that TrasGEX was safe and well tolerated, showing antitumor activity in 50% of evaluable patients, all of whom had progressive disease at the start of the study.
Bispecific antibody
Bispecific antibodies ( bsAbs ) are engineered monoclonal antibodies that contain two binding arms in a single molecule, targeting two different antigens.
In HER2+ tumors, several BSAbs are being evaluated in clinical trials.
MCLA-128 ( Merus ) is a humanized IgG1 bispecific antibody with enhanced ADCC activity targeting HER2 and HER3 to overcome HER3-mediated resistance and/or relapse in HER2 or EGFR-targeted therapy. In vitro, MCLA-128 demonstrated superior activity to trastuzumab and anti-HER3 antibodies.
Furthermore, MCLA-128 showed better ADCC enhancement in low HER2-expressing cell lines and in effector cells with low affinity FcγRIII.
In a phase I/II study for solid tumors ( NCT02912949 ) that included 8 heavily pretreated patients with metastatic BC, 1 patient had a partial response and 5 patients had stable disease.
Overall, the clinical benefit rate was 70%. MCLA-128 was well tolerated and the most common adverse reactions were grade 1-2.
Currently, a Phase II study ( NCT03321981 ) is underway evaluating the efficacy of MCLA-128 in combination with trastuzumab and chemotherapy in HER2-positive patients.
Zanidatamab-ZW25 is a HER2-targeted dual antibody that binds to two different epitopes in the extracellular domain of HER2.
Compared to trastuzumab, ZW25 shows enhanced tumor cell binding, blocks ligand-dependent and independent growth, and improves receptor internalization and down-regulation, and it is also expressed in a HER2-low expressing cell line model Antitumor activity.
In a phase 1 basket trial ( NCT02892123 ), a single dose of ZW25 had antitumor activity and a favorable safety profile with no dose-limiting toxicities.
Overall, the partial response rate was 33% ( 6/18 ) and the disease control rate was 50%.
The most common toxicities were grade 1-2 diarrhea and infusion reactions. A study of Zanidatamab in combination with palbociclib and fulvestrant in patients with HER2+/HR+ advanced BC is ongoing ( NCT04224272 ).
GBR1302 ( Glenmark Pharmaceuticals ) is a HER2xCD3 dual antibody for targeting T cells to HER2-expressing tumor cells.
The antitumor activity of GBR1302 has been demonstrated in preclinical studies, and it also inhibits the growth of JIMT-1 cells that are insensitive to trastuzumab inhibition.
Currently, a phase 1 clinical trial of GBR1302 monotherapy in advanced HER2-positive solid tumors with progression on anti-HER2 therapy is ongoing ( NCT02829372 ).
P95HER2 is a T-cell-directed dual antibody against P95HER2, a truncated form of Her2 , which has demonstrated anti-tumor effects in HER2-positive BC in vitro and in vivo.
Tribody [(HER2)2xFcRIII] contains two HER2-specific single chain antibody fragments, and a fragment that binds to the FcγRIII antigen.
It has shown advantages in triggering γδ T cell and NK cell-mediated lysis of HER2-expressing tumor cells, such as pancreatic ductal adenocarcinoma, BC, and primary ovarian tumors.
Her2(Per)-S-Fab was constructed by linking the Fab portion of pertuzumab to an FcγRIIIA single-domain antibody.
Preclinical evidence suggests that it has strong cytotoxicity against Her2-positive tumor cells.
In addition, in vitro and in vivo studies have also reported that this antibody may be clinically active in tumors with low or mild HER2 expression and can overcome tumor resistance to trastuzumab.
Ertumaxomab is a trifunctional double antibody that binds HER2 and CD3, respectively, and the FC moiety binds FcγRI, FcγRIIA, and FcγRIII.
Thus, the activity of Ertumaxomab induces a ternary complex between lymphoid T cells, tumor cells and stromal cells. This dual antibody binds to another epitope on the outer surface of HER2 cells ( unlike trastuzumab and pertuzumab ).
Ertumaxomab showed a 30% antitumor response rate and a favorable safety profile in a Phase I clinical trial in patients with HER2-positive tumors.
MM-111 is a dual antibody that specifically binds HER2/HER3, and in HER2 cell lines, MM-111 has shown efficacy in cells that are resistant to existing anti-HER2 therapies.
In a phase I clinical trial including 86 patients with different tumors, the combination of MM-111 with trastuzumab or lapatinib was well tolerated, with a clinical benefit rate of 55%.
This evidence supports an ongoing Phase 2 clinical trial.
sPD-L1xrErbB2 , a dual antibody targeting PD-L1 and Her2, elicits an anti-tumor immune response in Her2-overexpressing tumor cells.
BsPD-L1xreRB2 also induces IFN-γ activity, enhances the effect of ADCC, and increases intratumoral CD8+ T lymphocyte infiltration by blocking PD-1/PD-L1.
HER2Bi-aATCs , a CD3xHer2 dual antibody, were evaluated in a phase I clinical trial to evaluate the efficacy and safety of HER2Bi-aATCs combined with IL-2 and GM-CSF in 23 patients with advanced BC.
The results showed that the combination was well tolerated ( no dose-limiting adverse events ), with a clinical benefit rate of 59.1% and a median OS of 36.2 months.
MDX-210 is a dual antibody targeting FcγRI and HER2, by which it can activate effector cells, such as monocytes and macrophages, and promote antitumor activity against HER2-overexpressing tumor cells.
MDX-210 was evaluated in a Phase Ia/lb trial in patients with advanced BC or HER2-overexpressing ovarian cancer.
The results showed that the double antibody has a good safety profile, with one partial response and one mixed tumor response observed in patients with evaluable disease ( 10 patients ).
Summary
In recent years, immunotherapy has become the mainstay of cancer treatment.
Understanding the important role of ADCC in innate and adaptive tumor immune responses to monoclonal antibodies will allow us to target HER2+ BC in conjunction with these types of therapies.
This can be further enhanced by cancer treatments such as chemotherapy, radiation therapy or surgery.
Several promising combination strategies are currently being developed preclinically and clinically to enhance the ADCC response of NK cells to tumors, and it is believed that these drugs and combination strategies will significantly improve patient survival in the treatment of Her2-positive tumors.
References:
1. Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era. Breast. 2021 Dec; 60: 15–25.
What is the Immunotherapy targeting ADCC for HER2+ breast cancer?
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