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Fu, Y.; Zhang, Z.; Webster, K.A.; Paulus, Y.M. Treatment Strategies for Anti-VEGF Resistance in neovascular AMD. Encyclopedia. Available online: https://encyclopedia.pub/entry/56122 (accessed on 16 April 2024).
Fu Y, Zhang Z, Webster KA, Paulus YM. Treatment Strategies for Anti-VEGF Resistance in neovascular AMD. Encyclopedia. Available at: https://encyclopedia.pub/entry/56122. Accessed April 16, 2024.
Fu, Yingbin, Zhao Zhang, Keith A. Webster, Yannis M. Paulus. "Treatment Strategies for Anti-VEGF Resistance in neovascular AMD" Encyclopedia, https://encyclopedia.pub/entry/56122 (accessed April 16, 2024).
Fu, Y., Zhang, Z., Webster, K.A., & Paulus, Y.M. (2024, March 11). Treatment Strategies for Anti-VEGF Resistance in neovascular AMD. In Encyclopedia. https://encyclopedia.pub/entry/56122
Fu, Yingbin, et al. "Treatment Strategies for Anti-VEGF Resistance in neovascular AMD." Encyclopedia. Web. 11 March, 2024.
Treatment Strategies for Anti-VEGF Resistance in neovascular AMD
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Despite extensive use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics for over a decade, neovascular age-related macular degeneration (nAMD) or choroidal neovascularization (CNV) continues to be a major cause of irreversible vision loss in developed countries. Many nAMD patients demonstrate persistent disease activity or experience declining responses over time despite anti-VEGF treatment. The underlying mechanisms of anti-VEGF resistance are poorly understood, and no effective treatment strategies are available to date. Emerging strong evidence from animal models and clinical studies supports the roles of neovascular remodeling and arteriolar CNV formation in anti-VEGF resistance. Cholesterol dysregulation, inflammation, and ensuing macrophage activation are critically involved in arteriolar CNV formation and anti-VEGF resistance. Combination therapy by neutralizing VEGF and enhancing cholesterol removal from macrophages is a promising strategy to combat anti-VEGF resistance in CNV.

choroidal neovascularization CNV anti-VEGF resistance neovascular age-related macular degeneration AMD arteriolar CNV anti-VEGF therapies capillary CNV AIBP apoA-I

1. Limitation of Anti-VEGF Therapies

Age-related macular degeneration (AMD) stands as the leading cause of irreversible blindness among the elderly. In 2020, the number of individuals affected by AMD reached 196 million, with a projection to escalate to 288 million by 2040, imposing a substantial burden on global healthcare systems [1]. Neovascular AMD (nAMD), also known as choroidal neovascularization (CNV), constitutes 10–20% of AMD cases, yet it is responsible for 80–90% of AMD-related blindness [2]. The primary approach in current first-line therapy focuses on inhibiting vascular endothelial growth factor (VEGF), a potent angiogenic factor that stimulates vessel growth and increases vascular permeability.
Despite advancements, up to 50% of patients exhibit incomplete responses to existing anti-VEGF treatments, characterized by persistent fluid, unresolved or new hemorrhage, with suboptimal long-term outcomes even among those who initially respond [3][4][5][6][7][8][9][10][11][12][13][14]. Notably, studies such as Comparisons of Age-Related Macular Degeneration Treatments Trials (CATT) demonstrated persistent retinal fluid accumulation in a substantial percentage of patients treated with bevacizumab (67.4%) and ranibizumab (51.5%) after two years of treatment [3]. In the VIEW 1 and VIEW 2 trials, 19.7–36.6% of patients experienced active exudation after one year of regular 2.0 mg aflibercept treatments [6]. The SEVEN-UP study, focusing on patients exiting the MARINA or ANCHOR trials, revealed a gradual decline in mean visual acuity during long-term follow-up with pro re nata (PRN) retreatment [7]. Even patients initially responsive to treatment face challenges, as resistance can develop over time (known as tachyphylaxis) [4][15][16][17]. Studies on nAMD patients treated with bevacizumab showed a gradual decline in response, unaffected by increased dosage [18][19][20]. Similarly, patients treated with ranibizumab experienced recurrence in 66% to 76% of cases following 12–24 months of repeated treatment [21][22].
Various strategies, such as high-dose treatment [19][23][24][25] and switching between anti-VEGF biologics [26][27], have been explored in small-scale studies to address anti-VEGF resistance, demonstrating some success over limited follow-up periods. However, the initial anatomical improvements achieved through the transition to higher-dose therapy tend to plateau over time, resulting in only moderate enhancements in central retinal thickness (CRT) and minimal or negligible gains in visual acuity [25][28]. Studies have shown mild improvement in CRT with either no or only small gains in visual acuity following these interventions [26][28]. In a recent National Institute of Health (NIH)-sponsored trial comparing high doses of bevacizumab, ranibizumab, and aflibercept for treatment-resistant nAMD, no significant benefits were observed in any group, and there was no reduction in injection frequency (remaining at one injection every 5.7–6.4 weeks) [29]. Considering the lack of a substantial response and the potential theoretical risks associated with higher-volume injections, further research is recommended before advocating for the use of even higher dosages of these anti-VEGF agents delivered via standard formulations. Intriguingly, there is a notable similarity in the response to higher dosages of the same therapy and the approach of anti-VEGF switching. This observation suggests that additional common mechanisms contribute to anti-VEGF resistance that are not effectively addressed solely by targeting VEGF.
Combination therapies that simultaneously target VEGF and alternate pro-angiogenic signaling pathways have been explored in clinical trials. Attempts to combine ranibizumab with pegpleranib (Fovista) or nesvacumab, acting as antagonists for platelet-derived growth factor (PDGF) or angiopoietin 2 (Ang2), respectively, failed to meet endpoints [30][31]. Faricimab (Vabysmo), a bispecific antibody targeting both VEGF-A and Ang2, administered at extended treatment intervals (every 16 weeks), demonstrated clinical equivalence (i.e., “no inferiority”) to aflibercept given at 8-week intervals for nAMD, thereby reducing treatment burden for patients [32]. However, there is no evidence showing that faricimab provided significantly improved benefits in treating anti-VEGF-resistant patients. In fact, a recent study has shown that anti-VEGF treatment (e.g., aflibercept, brolucizumab, ranibizumab) also suppresses several key growth factors such as PDGF and Ang2, thus the combined suppression of VEGF and PDGF or Ang2 may not provide optimal clinical benefits [33]. The durability advantage of faricimab may be partly accounted for by the higher molar doses of ranibizumab (the anti-VEGF arm of faricimab is ranibizumab [34]) [33]. Consistent with this, high-dose (8 mg) aflibercept (Eyelea HD) showed similar 12–16-week extended dosing intervals as faricimab in the PULSAR trial. Most ongoing clinical trials continue to target the VEGF pathway without addressing the mechanism(s) causing anti-VEGF resistance. Thus, the development of an effective therapy addressing anti-VEGF resistance remains a critical unmet clinical need.

2. Animal models of anti-VEGF resistance.

Multiple pivotal clinical trials (ANCHOR, MARINA, CATT) have shown that patients of advanced age with larger baseline CNV lesions are less responsive to anti-VEGF treatment and have worse outcomes [13][35][36][37]. Importantly, anti-VEGF resistance in CNV patients is frequently associated with arteriolar CNV, characterized by large-caliber branching arterioles, vascular loops, and anastomotic connections. The persistence of fluid leakage in arteriolar CNV likely results from increased exudation through poorly formed tight junctions at arteriovenous anastomotic loops, particularly during periods of elevated blood flow. In contrast, individuals responding well to anti-VEGF treatment typically exhibit capillary CNV, where VEGF-mediated permeability is the primary cause of leakage. Moreover, recurrent anti-VEGF treatment can induce vessel abnormalization, arteriolar CNV formation, and ultimately contribute to anti-VEGF resistance [14][38], suggesting a mechanism for acquired anti-VEGF resistance.

The researchers found that laser photocoagulation produces larger CNV lesions in aged mice that are markedly more resistant to anti-VEGF treatment compared with young mice [39][40][41]. Importantly, laser-induced CNV in young and old mice, respectively, mimics capillary and arteriolar CNV [9][40]. The researchers propose that laser-induced CNV in aged mice is a clinically relevant model of anti-VEGF resistance [39][40].

3. Capillary CNV versus Arteriolar CNV

The formation of capillary CNV shares features with capillary angiogenesis, wherein new capillary blood vessels sprout from preexisting vessels [9][42][43]. Retina ischemia upregulates VEGF (from RPE, Müller cells, infiltrating macrophages, etc.), which binds to the VEGFR2 receptor of endothelia cells to initiate new capillary vessel growth in the subretinal or sub-RPE space [31][44][45].
In contrast, arteriolar CNV formation shares common features with arteriogenesis—the growth and proliferation of pre-existing collateral arteries through remodeling of the vessel wall [46][47]. Unlike angiogenesis, which is highly dependent on VEGF, arteriogenesis is not VEGF-dependent and is mainly driven by shear stress from blood flow [48][49][50]. Arteriogenesis involves endothelial cell activation, basal membrane degradation, leukocyte invasion, proliferation of vascular cells, neointima formation, and changes of the extracellular matrix [51].
Markers of capillary and arteriolar CNV are commonly identified by ICGA and Optical Coherence Tomography Angiography (OCTA), which distinguishes capillary from arteriolar CNV based on the size, shape, and pattern of the lesions. Capillary CNV is characterized by slow-filling, capillary-type microvessels. Arteriolar CNV is characterized by high-flow, large-caliber feeder arteries that give rise to many branching arterioles and anastomotic loop connections with minimal capillary components [9].
Compelling evidence supports functional roles for monocytes and macrophages that infiltrate areas of collateral vessel development and orchestrate arteriogenic remodeling. For example, monocyte depletion in both rabbit and mouse models of hindlimb ischemia leads to impaired arteriogenesis that can be restored by injecting exogenous monocytes [52]. The effect is similar to the depletion of circulating monocytes in murine models that abrogates arteriolar but not capillary CNV in old nAMD mice (see below) [39].
Macrophages play crucial roles in arteriogenesis through multiple pathways, including upregulating matrix metalloproteinases (MMPs) that are essential for collateral artery growth. MMPs are present in and around growing collateral arteries and promote extracellular matrix remodeling and breakdown of the basement membrane. Macrophages also release cytokines such as TNFα that increase leukocyte recruitment and stimulate the proliferation of endothelial and smooth muscle cells by secreting bFGF, PDGF, and VEGF [53].
Based on OCTA studies of CNV patients treated with recurrent anti-VEGF therapies, Spaide proposed a mechanism of arteriolar CNV formation [14]. Anti-VEGF therapy closes many newly formed vessels, increasing vascular resistance for the entire vascular circuit. Increased vessel wall stress induces arteriogenesis in the remaining vessels, leading to an increase in vessel size. When anti-VEGF drugs wane, vascular sprouts regrow. Repeated anti-VEGF treatment prunes back new vessels and reinitiates the cycle. The result is the formation of high-flow, large-caliber vessels, branching arterioles, vascular loops, and anastomotic connections. Thus, arteriolar CNV formation is attributed to the treatment of current anti-VEGF therapies—periodic pruning of angiogenic vascular sprouts by VEGF inhibition with unchecked arteriogenesis [14].

4. Role of Macrophages in Anti-VEGF Resistance

Several lines of evidence suggest that the accumulation of intracellular lipids in old macrophages plays a critical role in anti-VEGF resistance. Firstly, decreased efficacy of anti-VEGF therapy with age correlates inversely with an age-dependent increase in intracellular lipids in macrophages [39]. Secondly, macrophage depletion in old mice converts arteriolar CNV to capillary CNV [9] and restores CNV sensitivity to anti-VEGF treatment [39]. Thirdly, macrophages in surgically excised human CNV membranes following bevacizumab treatment have increased density and proliferative activity [54], and the proportion of circulating CD11b+ monocytes correlates with the number of anti-VEGF injections in patients with nAMD and PCV [55]. The actions of lipid-laden macrophages are also consistent with the well-established roles of monocytes and macrophages in promoting arteriogenesis by releasing growth factors, proteases and chemokines that mediate structural remodeling of the extracellular matrices, cell proliferation, and migration [47][53][56][57]. Both preclinical and clinical studies are consistent with the involvement of neovascular remodeling, in which macrophages are known to play important roles in anti-VEGF resistance [9][14][56].
Consistent with the contributions of lipid-laden macrophages in human arteriolar CNV formation, McLeod et al. identified a high frequency of activated HLA-DR+ macrophages associated with arteriolar CNV in human postmortem CNV specimens (Figures 9 and 10 in Ref. [58]). In addition to lipid-containing microglial cells found in type 3 neovascularization [59], hyperreflective lipid-filled cells of monocyte origin (i.e., macrophages) have been detected in nAMD [60]. Curcio and colleagues suggest that these monocyte-derived cells filled with lipid droplets resemble foam cells in coronary artery plaques [60], which are well-known to promote inflammation in association with atherosclerosis. Oxidized lipoproteins and macrophages were colocalized with CNV lesions, and most macrophages in the CNV membranes expressed oxidized lipoprotein-specific scavenger receptors, suggesting a close link between oxidized lipoproteins and macrophages in AMD [61]. Transcriptomic profiling showed that impaired cholesterol homeostasis is perturbed in aged macrophages and that oxysterol signatures in patient samples distinguish AMD from physiologic aging [62]. Expression of ABCA1 and cholesterol efflux are reduced in aged macrophages in mice and humans (old people and AMD) [63], and ABCA1 polymorphisms are associated with advanced AMD [64]. Multiple studies confirm the involvement of dysregulated lipid metabolism, macrophages, and inflammation in CNV [54][62][63][65][66][67][68][69][70][71][72][73][74][75][76][77], as well as the beneficial roles of lipid-lowering medications in reducing the risk of CNV, diabetic retinopathy, and diabetic macular edema [78][79][80][81]. It should be stressed that it can be difficult to definitively distinguish between microglia and macrophages by in vivo imaging of human patients. Although our macrophage depletion experiments suggest that blood-derived macrophages contribute to anti-VEGF resistance [39], retinal microglia may also be involved in anti-VEGF resistance.

5. Treatment Strategies for Anti-VEGF Resistance by Simultaneously Targeting Capillary and Arteriolar CNV

Our results suggest that while VEGF-dependent capillary angiogenesis is dominant in the CNV pathogenesis of young mice, inflammation-dependent neovascular remodeling and arteriolar CNV formation involving macrophages become dominant in aged mice and contribute to anti-VEGF resistance. Therefore, an effective treatment strategy requires the targeting of both capillary and arteriolar CNV. Because CNV is driven by abnormal levels of angiogenesis and inflammation with critical roles for VEGF-A, endothelial cells, and macrophages, the researchers explored a new treatment strategy that targets each of these central elements to address the limitations of current anti-VEGF [39][40].
Cholesterol-rich lipid rafts harboring activated receptors (e.g., VEGFR2, TLR4) serve as the organizing platform to initiate angiogenic and inflammatory signaling [82][83][84][85]. Extracellular apolipoprotein A-I (apoA-I) binding protein (AIBP) regulates lipid rafts via augmenting cholesterol efflux from endothelial cells, macrophages, and T cells, resulting in inhibition of angiogenesis and atherosclerosis, etc. [39][86][87][88][89][90][91][92][93]. AIBP binds its partner apoA-I or high-density lipoprotein (HDL), to enhance cholesterol efflux and inhibit lipid raft-anchored VEGFR2 signaling in endothelial cells [39][86]. By binding to the Toll-like receptor 4 (TLR4), AIBP/apoA-I augments cholesterol efflux from macrophages and microglia, normalizes plasma lipid rafts, and suppresses inflammation [87][88][94][95]. The ability of AIBP to target both hyperactive endothelial cells and cholesterol-laden macrophages makes it an ideal candidate to address the challenge of anti-VEGF resistance in CNV treatment. The researchers found that a combination of AIBP/apoA-I and anti-VEGF treatment ameliorated anti-VEGF resistance to aflibercept in experimental CNV in old mice by robustly inhibiting arteriolar CNV (Figure 1) [40]. Despite sharing endothelial VEGFR2 signaling as a common target, combined AIBP and anti-VEGF provide synergistic therapeutic benefits for CNV. This is because macrophages that are recruited by VEGF to lesion sites of inflammation secrete additional VEGF and other pro-angiogenic factors, thereby creating strong positive feedback loops [68][69][96]. Thus, both anti-VEGF agents and AIBP are required to interrupt the vicious cycle of events initiated by the reciprocal causal nexus of VEGF and inflammation.
Figure 1. Comparison between aflibercept and combination therapy (AIBP, apoA-I, and aflibercept) in suppressing laser-induced CNV in old mice. Representative (A) FA, (B) ICGA, and (C) Alexa 568 isolectin labeled RPE/choroid flatmounts of CNV lesions after treatments. (D) CNV vessel type quantification based on isolectin-B4 staining. The numbers inside the bars indicate the number of CNV laser spots. (E) Quantitative results of the percentage increase of fluorescent area in CNV lesions between the early and late phases of FA. (F) Quantitative results of normalized CNV area. Old mice were treated on day 2 (AE) and were analyzed at day 7 post laser injury. White and yellow dashed circles indicate arteriolar CNV in control and aflibercept treated mice. Green dashed circles indicate mixed type CNV in combination therapy treated mice in B and C. Mice treated on day 4 showed similar results. Bars represent mean ± SD. NS, p > 0.05; *, p < 0.05; ***, p < 0.001; ****, p < 0.0001. Adapted from Ref. [40].
As discussed above, macrophages may have varying roles in CNV. How can we ensure the proposed combination therapy only targets pathological macrophages? This is achieved through the selectivity and normalization properties of AIBP on the lipid rafts of activated target cells. Previous studies have shown that AIBP selectively targets lipid rafts of activated macrophages/microglia and inhibits inflammatory signaling by binding to activated (e.g., dimerized) TLR4 [82][94][95]. AIBP normalizes lipid rafts of activated macrophages/microglia (i.e., inflammarafts [82]) [94], reducing the proinflammatory and proangiogenic subtypes (i.e., pathogenic) without affecting normal macrophage function, including their protective functions.

6. How does the combination therapy compare with anti-VEGF gene therapy and higher dose anti-VEGF regimen currently in development?

AMD is a complex multi-factorial disease. It is unrealistic to expect that targeting one factor or one pathway will solve all the problems. The anti-VEGF gene therapy and higher dose regimen that are currently in development target VEGF-dependent angiogenesis without targeting arteriogenesis, which are unlikely to resolve resistance (see Discussion regarding high dose regimen in 1. Limitation of anti-VEGF therapies). In the HARBOR trial, high dose ranibizumab (2.0 mg) did not increase efficacy in treatment-naïve patients [97]. In the recently completed PULSAR trial, 8 mg aflibercept sustained improvements of visual acuity and retinal anatomy at 22 months with 36% fewer injections relative to the standard 2-mg dose, suggesting the potential to reduce treatment burdens. However, there is no evidence that the high-dose aflibercept eliminates anti-VEGF resistance. Rather, there is evidence that unbalanced treatments targeting VEGF-dependent angiogenesis alone can cause vessel abnormalization, arteriolar CNV formation, and anti-VEGF resistance [14][38] (Figure 2). Combination therapy has an advantage by targeting both angiogenesis and arteriogenesis.

Comparison of anti-VEGF monotherapy with AIBP/apoA-I/anti-VEGF combination therapy in the treatment of CNV

Figure 2. Comparison of anti-VEGF monotherapy with AIBP/apoA-I/anti-VEGF combination therapy in the treatment of CNV. Anti-VEGF therapies neutralize VEGF, inhibit VEGFR2 signaling in endothelial cells, and thereby inhibit angiogenesis and capillary CNV. However, this treatment results in unchecked arteriogenesis, vessel abnormalization, and arteriolar CNV formation, leading to anti-VEGF resistance and sub-optimal CNV management. In AIBP/apoA-I/anti-VEGF combination therapy, AIBP binds to activated TLR4 and augments cholesterol efflux from macrophages and microglia to apoA-I, normalizing plasma lipid rafts and suppressing inflammation, which inhibits arteriolar CNV. Simultaneously, anti-VEGF therapies inhibit VEGFR2 signaling in endothelial cells, thereby suppressing angiogenesis and capillary CNV. Thus, the combination therapy leads to the amelioration of anti-VEGF resistance and optimal CNV management.

7. Perspectives

Because long-term efficacy of anti-VEGF therapy is suboptimal and repeated anti-VEGF treatment can lead to arteriolar CNV and anti-VEGF resistance [14][38], The researchers predict that combination therapy with AIBP/apoA-I/anti-VEGF not only overcomes anti-VEGF resistance for monotherapy non-responders, but also improves therapeutic efficacy at all levels of anti-VEGF response in the treatment of nAMD. To our knowledge, there is no treatment available for arteriolar CNV. Combination therapy has the potential to replace current anti-VEGF monotherapies and become a new first-line therapy. The global anti-VEGF therapeutics market size was valued at USD 12.3 billion in 2022 and is estimated to reach USD 13.7 billion by 2031, representing a significant portion of global healthcare cost. The researchers' objective is to generate preclinical efficacy and safety data to support an Investigational New Drug (IND) application for AIBP/apoA-I/aflibercept therapy and advance to a first-in-human Phase I clinical trial that will ultimately benefit a wide range of nAMD patients including anti-VEGF non-responders and responders with sub-optimal long-term efficacy.

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