Patent Publication Number: US-2022211870-A1

Title: Paclitaxel-albumin-binding agent compositions and methods for using and making the same

Description:
FIELD OF THE INVENTION 
     This application relates to novel compositions of binding agents and carrier proteins and methods of making and using the same, in particular, as a cancer therapeutic. 
     BACKGROUND 
     Chemotherapy remains a mainstay for systemic therapy for many types of cancer, including melanoma. Most chemotherapeutic agents are only slightly selective to tumor cells, and toxicity to healthy proliferating cells can be high (Allen T M. (2002)  Cancer  2: 750-763), often requiring dose reduction and even discontinuation of treatment. In theory, one way to overcome chemotherapy toxicity issues as well as improve drug efficacy is to target the chemotherapy drug to the tumor using antibodies that are specific for proteins selectively expressed (or overexpressed) by cancer cells to attract targeted drugs to the tumor, thereby altering the biodistribution of the chemotherapy and resulting in more drug going to the tumor and less affecting healthy tissue. Despite 30 years of research, however, specific targeting rarely succeeds in the therapeutic context. 
     Conventional antibody dependent chemotherapy (ADC) is designed with a toxic agent linked to a targeting antibody via a synthetic protease-cleavable linker. The efficacy of such ADC therapy is dependent on the ability of the target cell to bind to the antibody, the linker to be cleaved, and the uptake of the toxic agent into the target cell. Schrama, D. et ai, (2006)  Nature reviews. Drug discovery  5:147-159. 
     Antibody-targeted chemotherapy promised advantages over conventional therapy because it provides combinations of targeting ability., multiple cytotoxic agents, and improved therapeutic capacity with potentially less toxicity. Despite extensive research, clinically effective antibody-targeted chemotherapy remains elusive: major hurdles include the instability of the linkers between the antibody and chemotherapy drug, reduced tumor toxicity of the chemotherapeutic agent when bound to the antibody, and the inability of the conjugate to bind and enter tumor cells. In addition, these therapies did not allow for control over the size of the antibody-drug conjugates. 
     There remains a need in the art for antibody-based cancer therapeutics that retain cytotoxic effect for targeted drug delivery to provide reliable and improved anti-tumor efficacy over prior therapeutics. 
     SUMMARY 
     According to the the present invention are disclosed nanoparticles which contain (a) carrier protein, (b) optionally a binding agent, and (c) paclitaxel, wherein the paclitaxel is present in an amount that is less than an amount that provides a therapeutic effect, and optionally (d) a therapeutic agent. Some aspects of the current invention are predicated, in part, on the idea that a reduced amount of paclitaxel, for example compared to that in albumin-bound nanoparticles such as ABRAXANE®, facilitates the formation of a complex of a carrier protein, such as albumin, with a binding agent, such as an antibody, to provide a stable nanoparticle. These nanoparticles may be referred to herein as “reduced toxicity nanoparticles” (RTP) or RTP complexes. 
     Also disclosed herein are nanoparticles which contain (a) carrier protein (b) a paclitaxel derivative, the paclitaxel derivative having reduced toxicity compared to paclitaxel, and optionally (c) a binding agent and/or (d) a therapeutic agent. 
     Further described herein are nanoparticle compositions, and methods of making and using the nanoparticles. 
     In one aspect is provided a nanoparticle comprising albumin and a paclitaxel derivative, wherein the paclitaxel derivative is less toxic than paclitaxel. In one embodiment, the paclitaxel derivative is a Meerwein Product of Paclitaxel. In a preferred embodiment, the paclitaxel derivative is 20-acetoxy-4-deactyl-5-epi-20, O-secotaxol. In one embodiment, the paclitaxel derivative is Baccatin III (2β, 5α, 7α, 10α, 13β)-4,10-Diacetoxy-1,7,13-trihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate). In one embodiment, the nanoparticle is held together by non-covalent bonds between the albumin and the paclitaxel derivative. In one embodiment, the albumin and the paclitaxel derivative have a relative weight ratio of less than about 10:1. In one embodiment, the nanoparticles do not comprise paclitaxel. 
     In one embodiment is provided a nanoparticle complex comprising albumin and a paclitaxel derivative, and further comprises binding agents (e.g., antibodies) having an antigen-binding domain. In one embodiment, an amount of the binding agents (e.g., antibodies) are arranged on an outside surface of the nanoparticle complexes. In some embodiments, the binding agents are a substantially single layer of binding agents on all or part of the surface of the nanoparticle. In one embodiment, the binding agents are bound to the carrier protein by non-covalent bonds. Preferably, the binding agents are antibodies. 
     In one embodiment, the nanoparticle complex further comprises a therapeutic agent. In one embodiment, die therapeutic agent is abiraterone, bendamustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everolimus, gefitinib, idarubicin, imatinib, hydroxyurea, irnatinib, lapatinib, icuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, sorafenib, vemurafenib, sunitinib, teniposide, triplatin, vinblastine, vinorelbine, vincristine, or cyclophosphamide. In one embodiment, the therapeutic agent is an agent listed in Table 2. 
     In one aspect is provided a nanoparticle composition comprising the nanoparticles or nanoparticle complexes as described herein. 
     In one aspect is provided a nanoparticle comprising a carrier protein (e.g., albumin) and paclitaxel, wherein the paclitaxel is is present in an amount that is less than an amount that provides a therapeutic effect. In one embodiment, the nanoparticle is held together by non-covalent bonds between the carrier protein and the paclitaxel. In one aspect, the nanoparticle complex was made by combining the carrier protein (e.g., albumin) and paclitaxel at a relative weight ratio of greater than about 10:1 carrier protein to paclitaxel. 
     In one embodiment, the amount of paclitaxel present in the nanoparticles (nanoparticle complexes) or nanoparticle composition is greater than or equal to a minimum amount capable of providing stability to the nanoparticle complexes comprising a protein carrier (e.g., albumin) and paclitaxel. In one embodiment, the amount of paclitaxel present in the nanoparticles or nanoparticle composition is greater than or equal to a minimum amount capable of providing affinity of the paclitaxel with the protein carrier (e.g., albumin). In one embodiment, the amount of paclitaxel present in the nanoparticles or nanoparticle composition is greater than or equal to a minimum amount capable of facilitating complex formation of the paclitaxel and the protein carrier (e.g., albumin). 
     The ratio of albumin to paclitaxel in the nanoparticles or nanoparticle composition preferably is less than that present in ABRAXANE®. ABRAXANE® contains 100 mg paclitaxel for about 900 mg albumin. In one embodiment, the weight ratio of the carrier protein (e.g., albumin) to paclitaxel in the nanoparticle composition is greater than about 9:1. In one embodiment, the weight ratio is greater than about 10:1, or 11:1, or 12:1, or 13:1, or 14:1, or 15:1, or about 16:1, or about 17:1, or about 18:1, or about 19:1, or about 20:1, or about 21:1, or about 22:1, or about 23:1, or about 24:1, or about 25:1, or about 26:1, or about 27:1, or about 28:1, or about 29:1, or about 30:1, in one embodiment, the weight ratio of the carrier protein to paclitaxel in the nanoparticle complex is greater than about 9:1. In one embodiment, the weight ratio is greater than about 10:1, or 11:1, or 12:1, or 13:1, or 14:1, or 15:1, or about 16:1, or about 17:1, or about 18:1, or about 19:1, or about 20:1, or about 21:1, or about 22:1, or about 23:1, or about 24:1, or about 25:1, or about 26:1, or about 27:1, or about 28:1, or about 29:1, or about 30:1. 
     In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of providing stability to the nanoparticle complexes comprising a protein carrier (e.g., albumin) and paclitaxel, and optionally at least one therapeutic agent. In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of providing affinity of the at least one therapeutic agent to the protein carrier. In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of facilitating complex formation of the at least one therapeutic agent and the protein carrier. 
     In any of the embodiments, the amount of paclitaxel can be less than a therapeutic amount for paclitaxel. In other words, the amount can be less than what is provided or contemplated for providing a therapeutic benefit, such as for example, a chemotherapeutic amount to effectively treat a cancer. 
     In one embodiment, the amount of paclitaxel present in the nanoparticle composition is less than about 5 mg/mL. In one embodiment, the amount of paclitaxel present in the nanoparticle composition is less than about 4.54 mg/mL, or about 4.16 mg/mL, or about 3.57 mg/mL, or about 3.33 mg/mL, or about 3.12 mg/mL, or about 2.94 mg/mL, or about 2.78 mg/mL, or about 2.63 mg/mL, or about 2.5 mg/mL, or about 2.38 mg/mL, or about 2.27 mg/mL, or about 2.17 mg/mL, or about 2.08 mg/mL, or about 2 mg/mL or about 1.92 mg/mL, or about 1.85 mg/mL, or about 1.78 mg/mL, or about 1.72 mg/mL, or about 1.67 
     Without being bound by theory, it is contemplated that binding to the carrier protein, e.g., complexation of the binding agent to the carrier protein, occurs through an albumin-binding motif on the binding agents and/or an antibody-binding motif on the carrier protein, In one embodiment, the binding agent comprises an albumin-binding motif. In one embodiment, the carrier protein comprises an antibody-binding motif. Non-limiting examples of antibody-binding motifs can be found in PCT Application No, PCT/US2017/045643, filed Aug. 4, 2017, which is incorporated herein by reference in its entirety. In some embodiments, the binding agent is a non-therapeutic and non-endogenous human antibody, a fusion protein, e.g., fusion of an antibody Fc domain to a peptide that binds a target antigen, or an aptamer. 
     In one embodiment, the binding agent comprises an antigen-binding domain. In one embodiment, the antigen is CD3, CD19, CD20, CD38, CD30, CD33, CD52, PD-1, PD-L1, PD-L2, CTLA-4, RANK-L, GD-2, Ly6E, HER3, EGFR, DAF, ERBB-3 receptor, CSF-1R, HER2, STEAP1, CD3, CEA, CD40, OX40, Ang2-VEGF, or VEGF. 
     Tin one embodiment, the binding agent is an antibody selected from ado-trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizuniab, cetuximab, denosumab, dinutuximab, ipilimumab, nivolumab, obinutuzumab, ofatumumab, panitumurnab, pembrolizuniab, pertuzumab, rituximab, Ramucirumab, avelumab or durvaiumab, pidilizumab, BMS 936559, OKT3, and trastuzumab. 
     The invention further includes lyophilized nanoparticles and nanoparticle compositions, and lyophilized nanoparticles and compositions that do not materially differ from, or are the same as, the properties of freshly-prepared nanoparticles. In particular, the lypholized composition, upon resuspending in aqueous solution, is similar or identical to the fresh composition in terms of particle size, particle size distribution, toxicity for cancer cells, binding agent affinity, and binding agent specificity, Surprisingly, lyophilized nanoparticles retain the properties of freshly-made nanoparticles after resuspension, notwithstanding the presence of two different protein components in these particles. In one embodinlent, the lyophilized composition is stable at room temperature for at least about 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. in one embodiment, the lyophilized composition is stable at room temperature for at least 3 months. In one embodiment, the reconstituted nanoparticles retain the activity of the therapeutic agent and are capable of binding to the target in vivo. 
     In some embodiments, the at least one therapeutic agent is located inside the nanoparticle. In other embodiments, the at least one therapeutic agent is located on the outside surface of the nanoparticle. In yet other embodiments, the at least one therapeutic agent is located inside the nanoparticle and on the outside surface of the nanoparticle. 
     In some embodiments, the nanoparticle contains more than one type of therapeutic agent. For example, a taxane and a platinum drug, e.g. paclitaxel and cisplatin. 
     In some embodiments, the nanoparticle further comprises at least one additional therapeutic agent that is not paclitaxel. In some embodiments, the at least one therapeutic agent is abiraterone, bendaniustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, eyerolimus, gefitinib, idarubicin, imatinib, hydroxyurea, imatinib, lapatinib, leuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, sorafenib, yernuralenib, sunitinib, teniposide, triplatin, vinblastine, vinorelbine, vincristine, or cyclophosphamide. 
     In some embodiments, the binding agents, carrier protein and/or, when present, therapeutic agent, are bound through non-covalent bonds. 
     In some embodiments, the carrier protein is selected from the group consisting of gelatin, elastin gliadin, legumin, zein, a soy protein, a milk protein, and a whey protein. In preferred embodiments, the carrier protein is albumin, for example, human serum albumin. 
     In some embodiments, the composition is formulated for intravenous delivery. In other embodiments, the composition is formulated for direct injection or perfusion into a tumor. 
     In some embodiments, the nanoparticles have a dissociation constant between about 1×10 −11  M and about 1×10 −9 M. 
     In one embodiment, provided herein are methods of making the nanoparticle compositions, wherein said method comprises contacting the carrier protein and the paclitaxel and the at least one therapeutic agent under conditions and ratios of components that will allow for formation of the desired nanoparticles. 
     In some aspects, provided herein are methods for forming an albumin-paclitaxel derivative or albumin-paclitaxel nanoparticle, wherein method comprises: homogenizing the albumin with paclitaxel derivative or paclitaxel in a solution under high pressure, to generate an albumin-paclitaxel derivative or albumin-paclitaxel nanoparticle. 
     In some aspects, provided herein are methods of making nanoparticle compositions, wherein said methods comprise contacting the carrier protein, the paclitaxel, and/or the therapeutic agent with the binding agents in a solution having a pH of between 5.0 and 7.5 and a temperature between about 5° C. and about 60° C., between about 23° C. and about 60° C., or between about 55° C. and about 60° C. under conditions and ratios of components that will allow for formation of the desired nanoparticles. In one embodiment, the nanoparticle is made between 55° C. and 60° C. and pH 7.0. In another aspect, provided herein are methods of making the nanoparticle compositions, wherein said method comprises (a) contacting the carrier protein, the paclitaxel and the therapeutic agent to form a core and (b) optionally contacting the core with the antibodies in a solution having a pH of about 5.0 to about 7.5 at a temperature between about 5° C. and about 60° C., between about 23° C. arid about 60° C., or between about 55° C. and about 60° C. under conditions and ratios of components that will allow for formation of the desired nanoparticles. 
     In some aspects, an amount of a therapeutic agent (e.g., a therapeutic agent which is not paclitaxel) can also be added to the carrier protein. 
     In further embodiments, the nanoparticles are made as above, and then lyophilized. 
     In another aspect, provided herein are methods for treating a cancer cell, the method comprising contacting the cell with an effective amount of a nanoparticle composition disclosed herein to treat the cancer cell. 
     In one embodiment is provided a method for killing cancer cells in a population of cancer cells, the method comprising contacting the cells with an effective amount of a nanoparticle composition, wherein said composition is maintained in contact with said cells for a sufficient period of time to kill cancer cells, wherein said nanoparticle composition comprises nanoparticle complexes, each of the nanoparticles comprising albumin and paditaxel, wherein the paclitaxel is present in an amount that is less than an amount that provides a therapeutic effect. 
     In one embodiment is provided a method for treating cancer in patient in need thereof, the method comprising administering to the patient a nanoparticle composition comprising nanoparticle complexes, each of the nanoparticles comprising albumin and paclitaxekwherein the paclitaxel is present in an amount that is less than an amount that provides a therapeutic effect. 
     In another aspect, provided herein are methods for treating a tumor in a patient in need thereof, the method comprising contacting the cell with an effective amount of a nanoparticle composition disclosed herein to treat the tumor. In some embodiments, the size of the tumor is reduced. In other embodiments, the nanoparticle composition is administered intravenously. In yet other embodiments, the nanoparticle composition is administered by direct injection or perfusion into the tumor. 
     In some embodiments, the methods provided herein include the steps of: a) administering the nanoparticle composition once a week for three weeks; b) ceasing administration of the nanoparticle composition for one week; and c) repeating steps a) and b) as necessary to treat the tumor. 
     In some embodiments, the therapeutically effective amount comprises about 75 mg/m 2  to about 175 mg/m 2  of the carrier protein (i.e., milligrams carrier protein per m 2  of the patient). In other embodiments, the paclitaxel is of an amount that is less than about 75 mg/m 2 , such as between 5 mg/m 2  and 75 mg/m 2 . In other embodiments, the paclitaxel is of an amount that is less than a therapeutically effective amount. In some embodiments, the therapeutic agent is of a therapeutically effective amount. In some embodiments, the therapeutically effective amount comprises about 30 mg/m 2  to about 70 mg/m 2 of the binding. agent. In yet other embodiments, the therapeutically effective amount comprises about 30 mg/m 2  to about 70 mg/m 2 bevacizumab. 
     An embodiment of the invention includes a method for increasing the duration of tumor uptake of a chemotherapeutic agent by administering the chemotherapeutic agent in a nanoparticle comprising a carrier protein and the chemotherapeutic agent having surface complexation with an antibody, e,g., an antibody that specifically binds to an antigen on or shed by the tumor. 
    
    
     
       BRIEF DESCRIPTION OF TFIE DRAWINGS 
       The following figures are representative only of the invention and are not intended as a limitation. For the sake of consistency, the nanoparticles of this invention using ABRAXANE® and bevacizumab employ the acronym “AR” and the number after AB such as AB160 is meant to confer the average particle size of these nanoparticles (in nanometers). Likewise, when the binding agent is rituximab, the acronym is “AR” while the number thereafter remains the same. 
         FIG. 1  shows the reaction of paclitaxel withi Meetwein&#39;s Reagent to form the Meerwein&#39;s Product of Paclitaxel (20-Acetoxy-4-deactyl-5-epi-20, O-secotaxol). 
         FIGS. 2A-2E  show the nanoparticle diameter of non-toxic nanoparticles (NTP) alone ( FIG. 2A ) or incubated with 4 mg/mL ( FIG. 2B ), 6 mg/mL ( FIG. 2C ), 8 mg/mL ( FIG. 2D ) or 10 mg/mL ( FIG. 2E ) bevacizumab for 30 min. Diameter was measured at a 1:300 dilution using Malvern Nanosight technology. 
         FIGS. 3A and 3B  show the binding affinity (Kd) of bevacizumab ( FIG. 3A ) or rituximab ( FIG. 3B ) to NTP. Kd was measured using Bio Layer Interferometry Technology. 
         FIG. 4A  shows the stability of nanoparticle complexes in PBS.  FIG. 4B  shows the stability of nanoparticle complexes in serum. 
         FIGS. 5A-5E  show blocking of CD20-positive Daudi cells with isotype control ( FIG. 5A ), anti-CD20 antibody ( FIG. 5B ), ABPAXANE® ( FIG. 5C ), ARI60 ( FIG. 5D ), NTP ( FIG. 5E ), rituxitmab-bound NTP (NTRit;  FIG. 5F ), or rituximab alone ( FIG. 5G ). 
     
    
    
     DETAILED DESCRIPTION 
     After reading this description it will become apparent to one skilled in the art how to implement the invention in various alternative embodiments and alternative applications. However, all the various embodiments of the present invention will not be described herein. It will be understood that the embodiments presented here are presented by way of an example only, and not limitation. As such, this detailed description of various alternative embodiments should not be construed to limit the scope or breadth of the present invention as set forth below. 
     Before the present invention is disclosed and described, it is to be understood that the aspects described below are not limited to specific compositions, methods of preparing such compositions, or uses thereof as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. 
     The detailed description of the invention is divided into various sections only for the reader&#39;s convenience and disclosure found in any section may be combined with that in another section. Titles or subtitles may be used in the specification for the convenience of a reader, which are not intended to influence the scope of the present invention. 
     Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings: 
     The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. 
     “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. 
     The term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by (+) or (−) 10%, 5%,1%, or any subrange or subvalue there between. Preferably, the term “about” when used with regard to a dose amount means that the dose may vary by +/−10%. For example, “about 400 to about 800 binding agents” indicates that an outside surface of a nanoparticles contain an amount of binding agent between 360 and 880 particles. 
     “Comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of” when used to define compositions and methods., shall mean excluding other elements of any essential significance, to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention. 
     The term “nanoparticle” as used herein refers to particles having at least one dimension which is less than 5 microns, In preferred embodiments, such as for intravenous administration, the nanoparticle is less than 1 micron. For direct administration, the nanoparticle is larger. Even larger particles are expressly contemplated by the invention. 
     In a population of particles, the sizes of individual particles are distributed about a mean. Particle sizes for the population can therefore be represented by an average, and also by percentiles. D50 is the particle size below which 50% of the particles fall. 10% of particles are smaller than the D10 value and 90% of particles are smaller than D90. Where unclear, the “average” size is equivalent to D50. So, for example., AB160 and AR.160 refer to nanoparticles having an average size of 160 nanometers. 
     The term “nanoparticle” may also encompass discrete multimers of smaller unit nanoparticles. For 160 nm nanoparticles, multimers would therefore be approximately 320 nm, 480 nm, 640 nm, 800 nm, 960 nm, 1120 nm, and so on. 
     The term “carrier protein” as used herein refers to proteins that function to transport binding agents and/or therapeutic agents. The binding agents of the present disclosure can reversibly bind to the carrier proteins. Examples of carrier proteins are discussed in more detail below. 
     The term “core” as used herein refers to a central or inner portion of the nanoparticle which may be comprised of a carrier protein, a carrier protein and a therapeutic agent, or other agents or combination of agents. In some embodiments, an albumin-binding motif of the binding agent may be associated with the core. 
     The term “therapeutic agent” as used herein means an agent which is therapeutically useful, e.g., an agent for the treatment, remission or attenuation of a disease state, physiological condition, symptoms, or etiological factors, or for the evaluation or diagnosis thereof. A therapeutic agent may be a chemotherapeutic agent, for example, mitotic inhibitors, topoisomerase inhibitors, steroids, anti-tumor antibiotics, antimetabolites, alkylating agents, enzymes, proteasome inhibitors, or any combination thereof. 
     As used herein, the term, “binding agent”, “binding agent specific for”, or “binding agent that specifically binds” refers to an agent that binds to a target antigen and does not significantly bind to unrelated compounds. Examples of binding agents that can be effectively employed in the disclosed methods include, but are not limited to, lectins, proteins, and antibodies, such as monoclonal antibodies, e,g. humanized monoclonal antibodies, chimeric antibodies, or polyclonal antibodies, or antigen-binding fragments thereof, as well as aptamers fusion proteins, and aptamers having or fused to an albumin-binding motif. In an embodiment the binding agent is an exogenous antibody. An exogenous antibody is an antibody not naturally produced in a mammal, e.g. in a human, by the mammalian immune system. 
     The term “antibody” or “antibodies” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules (i.e., molecules that contain an antigen binding site that immuno-specifically bind an antigen). The term also refers to antibodies comprised of two immunoglobulin heavy chains and two immunoglobulin light chains as well as a variety of forms including full length antibodies and portions thereof; including, for example, an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab′, a F(ab′)2, Fv, a disulfide linked Fv, a scFv, a single domain antibody (dAb), a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, a bispecific antibody, a functionally active epitope-binding fragment thereof, bifunctional hybrid antibodies (e.g., Lanzavecchia et al.,  Eur. J Immunol.  17, 105 (1987)) and single chains (e.g., Huston et al.,  Proc. Nalt. Acad. Sci. US.A.,  85, 5879-5883 (1988) and Bird et al.,  Science  242, 423-426 (1988), which are incorporated herein by reference). (See, generally, Hood et al.,  Immunology,  Benjamin, N.Y., 2ND ed. (1984); Harlow and Lane,  Antibodies. A Laboratory Manual,  Cold Spring Harbor Laboratory (1988); Hunkapiller and Hood,  Nature,  323, 15-16 (1986), which are incorporated herein by reference). The antibody may be of any type (e.g., IgG, IgA, IgE or IgD). Preferably, the antibody is IgG. An antibody may be non-human (e.g., from mouse, goat, or any other animal), fully human, humanized, or chimeric. Antibody or antibodies include any biosimilar(s) of the antibodies disclosed herein. Biosimilars, as used herein, refers to a biopharmaceutical which is deemed to be comparable in quality, safety, and efficacy to a reference product marketed by an innovator company (Section 351(i) of the Public Health Service Act (42 U.S.C. 262(i)). 
     The term “dissociation constant,” also referred to as “K d ,” refers to a quantity expressing the extent to which a particular substance separates into individual components (e.g., the protein carrier, antibody, and a therapeutic agent). 
     The terms “lyophilized,” “lyophilization” and the like as used herein refer to a process by which the material (e.g., nanoparticles) to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment. An excipient is optionally included in pre-lyophilized formulations to enhance stability of the lyophilized product upon storage. In some embodiments, the nanoparticles can be formed from lyophilized components (carrier protein, paclitaxel, and optionally antibody and/or a therapeutic agent) prior to use as a therapeutic. In other embodiments, the carrier protein and paclitaxel, and optionally a binding agent, e.g., antibody, and/or a therapeutic agent are first combined to facilitate the formation of stable nanoparticles and then lyophilized. The lyophilized sample may further contain additional excipients. 
     The term “bulking agents” comprise agents that provide the structure of the freeze-dried product. Common examples used for bulking agents include mannitol, glycine, lactose and sucrose. In addition to providing a pharmaceutically elegant cake, bulking agents may also impart useful qualities in regard to modifying the collapse temperature, providing freeze-thaw protection, and enhancing the protein stability over long-term storage. These agents can also serve as tonicity modifiers. In some embodiments, the lyophilized compositions described herein comprise bulking agents. In some embodiments, the lyophilized compositions described herein do not comprise bulking agents. 
     The term “buffer” encompasses those agents which maintain the solution in an acceptable range prior to lyophilization and may include succinate (sodium or potassium), histidine, phosphate (sodium or potassium), Tris(tris(hydroxymethyl)aminomethane), diethanolamine, citrate (sodium) and the like. The buffer of this invention may have a pH in an the range from about 5.5 to about 6.5; and preferably has a pH of about 6.0. Examples of buffers that will control the pH in this range include succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers. 
     The term “cryoprotectants” generally includes agents which provide stability to the protein against freezing-induced stresses, presumably by being preferentially excluded from the protein surface. They may also offer protection during primary and secondary drying, and long-term product storage. Examples are polymers such as dextran and polyethylene glycol; sugars such as sucrose, glucose, trehalose, and lactose; surfactants such as polysorbates; and amino acids such as glycine, arginine, and serine. 
     The term “lyoprotectant” includes agents that provide stability to the protein during the drying or “dehydration” process (primary and secondary drying cycles), presumably by providing an amorphous glassy matrix and by binding with the protein through hydrogen bonding, replacing the water molecules that are removed during the drying process. This helps to maintain the protein conformation, minimize protein degradation during the lyophilization cycle and improve the long-term products. Examples include polyols or sugars such as sucrose and trehalose. 
     The term “pharmaceutical formulation” refers to preparations which are in such form as to permit the active ingredients to be effective, and which contains no additional components that are toxic to the subjects to which the formulation would be administered. 
     “Pharmaceutically acceptable” excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed. 
     “Reconstitution time” is the time that is required to rehydrate a lyophilized formulation into a solution. 
     A “stable” formulation is one in which the protein therein essentially retains its physical stability and/or chemical stability and/or biological activity upon storage. For example, various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and ,tones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature for a selected time period. 
     The term “epitope” as used herein refers to the portion of an antigen which is recognized by a binding agent, e.g., an antibody. Epitopes include, but are not limited to, a short amino acid sequence or peptide (optionally glycosylated or otherwise modified) enabling a specific interaction with a protein (e.g., an antibody) or ligand. For example, an epitope may be a part of a molecule to which the antigen-binding site of a binding agent attaches. 
     The term “treating” or “treatment” covers the treatment of a disease or disorder (e.g., cancer), in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disease or disorder; (iii) slowing progression of the disease or disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. In some embodiments “treating” or “treatment” refers to the killing of cancer cells. 
     The term “kill” or “killing” with respect to a cancer treatment includes any type of manipulation that will directly or indirectly lead to the death of that cancer cell or at least of portion of a population of cancer cells. 
     The term “aptamer” refers to a nucleic acid molecule that is capable of binding to a target molecule, such as a polypeptide. For example, an aptamer of the invention can specifically bind to e.g., CD20, CD38, CD52, PD-1, PD-L1, PD-L2, Ly6E, HER2, HER3/EGFR DAF, ERBB -3 receptor, CSF-1R, STEAP1, CD3, CEA, CD40, OX40, Ang2-VEGF and VEGF. The generation of antibodies with a particular binding specificity and the therapeutic use of aptamers are well established in the art. See, e.g., U.S. Pat. Nos. 5,475,096, 5,270,163, 5,582,981, 5,840,867, 6,011,020, 6,051,698, 6,147,204, 6,180,348 and 6,699,843, and the therapeutic efficacy of Macugen® (Eyetech, New York) for treating age-related macular degeneration, each of which is incorporated herein by reference in its entirety. 
     The term “oligomer” or “oligomeric” or “oligomerized” as used herein refers to oligomers composed of two or more monomers. 
     Fusion proteins are bioengineered polypeptides that join a protein or fragment thereof (e.g., the crystallizable fragment (Fc) domain of an antibody) with another biologically active agent (e.g., a protein domain, peptide, or nucleic acid or peptide aptamer) to generate a molecule with desired structure-function properties and significant therapeutic potential. The gamma immunoglobulin (IgG) isotype is often used as the basis for generating Fc-fusion proteins because of favorable characteristics such as recruitment of effector function and increased plasma half-life. Given the range of aptamers, both peptide and nucleic acids, that can be used as fusion partners, fusion proteins ave numerous biological and pharmaceutical applications. 
     The term “non-toxic nanoparticles” (NTPs) or “NTP complexes” refers to nanoparticles comprising a carrier protein (e.g., albumin) and a paclitaxel derivative that is less toxic than paclitaxel. Optionally, the NTPs or NTP complexes comprise binding agents (e.g., antibodies) and/or therapeutic agents (e.g., chemotherapeutic agents). 
     The phrase “less toxic than paclitaxel” refers to paclitaxel derivatives that exhibit reduced toxicity to (e.g., reduced killing of) cells, including cancer cells and normal cells, as compared to paclitaxel. For example, the Meerwein Product of Paclitaxel (20-Acetoxy-4-deactyl-5-epi-20, O-secotaxol) has significantly reduced toxicity, likely due to the breaking of the C-4,C-5 oxetane ring of paclitaxel. 
     The term “reduced toxicity nanoparticles” (RTPs) or “RTP complexes” refers to nanoparticles comprising a carrier protein (e.g., albumin) and a reduced amount of paclitaxel compared to ABRAXANE® (.g., an albumin:paclitaxel ratio of about 9:1). Optionally, the RTPs or RIP complexes comprise binding agents (e.g., antibodies) and/or therapeutic agents (e.g., chemotherapeutic agents). 
     Additionally, some terms used in this specification are more specifically defined below. 
     Overview 
     ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers. Paclitaxel can exist in the particles in a non-crystalline, amorphous state. ABRAXANE® can be supplied as, for example, a lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. A single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. 
     ABRAXANE® nanoparticles are stabilized albumin-bound paclitaxel. The association of the paclitaxel and albumin can be via, for example, hydrophobic interactions. In some examples, the nanoparticle are stable at an average size of 130 nm. It is also known that other hydrophobic drugs such as, for example, docetaxel, rapamycin, can similarly form stabilized nanoparticles by binding to albumin. 
     For conventional ADCs to be effective, it is critical that the linker be stable enough not to dissociate in the systemic circulation but allow for sufficient drug release at the tumor site. Alley, S. C., et al. (2008)  Bioconjug Chem  19:759-765. This has proven to be a major hurdle in developing effective drug conjugate (Julien, D.C., et al. (2011)  MAbs  3:467-478; Alley, S. C., et al. (2008)  Bioconjug Chem  19:759-765); therefore, an attractive feature of the nano-immune conjugate is that a biochemical linker is not required. 
     Another shortcoming of current ADCs is that higher drug penetration into the tumor has not been substantively proven in human tumors. Early testing of ADCs in mouse models suggested that tumor targeting with antibodies would result in a higher concentration of the active agent in the tumor (Deguchi, T. et al. (1986)  Cancer Res  46: 3751-3755); however, this has not correlated in the treatment of human disease, likely because human tumors are much more heterogeneous in permeability than mouse tumors, Jain, R. K. et al. (2010)  Nat Rev Clin Oncol  7:653-664. Also, the size of the nanoparticle is critical for extravasation from the vasculature into the tumor. In a mouse study using a human colon adenocarcinoma xenotransplant model, the vascular pores were permeable to liposomes up to 400 nm. Yuan, F., et al. (1995)  Cancer Res  55: 3752-3756. Another study of tumor pore size and permeability demonstrated that both characteristics were dependent on tumor location and growth status, with regressing tumors and cranial tumors permeable to particles less than 200 nm. Hobbs, S. K., et al., (1998)  Proc Natl Acad. Sci USA  95:4607-4612. The nano-immune conjugate described herein overcomes this issue by the fact that the large complex, which is less than 200 nm intact is partially dissociated in systemic circulation into smaller functional units that are easily able to permeate tumor tissue. Furthermore, once the conjugate arrives to the tumor site, the smaller toxic payload can be released and only the toxic portion needs to be taken up by tumor cells, not the entire conjugate. 
     The advent of antibody- (i.e. AVASTIN®) coated albumin nanoparticles containing a therapeutic agent (i.e., ABRAXANE®) has led to a new paradigm of directional delivery of two or more therapeutic agents to a predetermined site in vivo. See PCT Patent Publication Nos. WO 2012/154861 and WO 2014/055415, each of which is incorporated herein by reference in its entirety. 
     However, it is contemplated that some cancers will not be treated by the paclitaxel in the ABRAXANE®-antibody complexes, and/or that other therapeutic agents (e.g., anti-cancer chemotherapeutic agents) will be more effective in treating certain cancers. Herein are disclosed reduced toxicity nanoparticles (RIP) comprising a carrier protein (e.g., albumin) and a reduced amount of paclitaxel (e.g., compared to ABRAXANE®), or non-toxic nanoparticles (NTP) comprising a carrier protein (e.g., albumin) and a paclitaxel derivative that is less toxic than paclitaxel. The nanoparticles may further include a therapeutic agent and/or binding agents (e.g., antibodies). 
     Nanoparticles and Nanoparticle Compositions 
     As will be apparent to the skilled artisan upon reading this disclosure, the present disclosure relates to nanoparticles and compositions of nanoparticles containing a carrier protein (e.g, albumin) and a paclitaxel derivative (e.g., a derivative that is less toxic than paclitaxel) or a reduced amount of paclitaxel (e.g., compared to a therapeutic amount, and/or compared to an amount in ABRAXANE®). In some embodiments, the nanoparticles also contain binding agents and/or a therapeutic agent. In some embodiments, the nanoparticles or nanoparticle composition is lyophilized. 
     The present invention is further predicated, in part, on the formation of nanoparticles comprising a carrier protein and paclitaxel in a lower amount than is present in ABRAXANE® or a paclitaxel derivative that is less toxic (e.g., to cells) than paclitaxel, optionally with a binding agent and/or a therapeutic agent. Without being hound by theory, it is believed that such nanoparticles provide targeted therapy to a tumor while minimizing toxicity to the patient, and can be used to treat tumors that traditionally are not susceptible to paclitaxel and/or that respond better to a different therapeutic agent. 
     In some embodiments, the cation protein can be albumin, gelatin, elastin (including topoelastin) or elastin-derived polypeptides (e.g., α-elastin and elastin-like polypeptides (ELPs)), gliadin, legumin, zein, soy protein (e.g., soy protein isolate (SPI)), milk protein (e.g., β-lactoglobulin (BLG) and casein), or whey protein (e.g, whey protein concentrates (WPC) and whey protein isolates (WPI)). In preferred embodiments, the carrier protein is albumin. In preferred embodiments, the albumin is egg white (ovalbumin), bovine serum albumin (BSA), or the like. In even more preferred embodiments, the carrier protein is human serum albumin (HSA). In some embodiments, the carrier protein is a recombinant protein (e,g., recombinant HSA). In some embodiments, the carrier protein is a generally regarded as safe (GRAS) excipient approved by the United States Food and Drug Administration (FDA). 
     In some embodiments, the binding agents are antibodies selected from adotrastuzumab emtansine, alemtuzumab, atezolizumab, beyacizumab, cetuximab, denosumab, dinutuximab, nivolumab, obinutuzumab, ofatumumab, panitumuinab, petnbrolizumab, pertuzumab, rituximab, avelumab tar durvalumab, pidilizumab, BMS 936559, and trastuzumab. In some embodiments, the antibodies are selected from the antibodies listed in Table 1. In some embodiments, the antibodies are a substantially single layer of antibodies on all or part of the surface of the nanoparticle. 
     Table 1 depicts a list of non-limiting list of antibodies. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Antibodies 
               
            
           
           
               
               
            
               
                 Biologic 
                 Treatment(s)/Target(s) 
               
               
                   
               
               
                 Rituximab (Rituxan ®) 
                 Non-Hodgkin lymphoma 
               
               
                 AlemtuzumaB (Campath ®) 
                 Chronic lymphocytic leukemia (CLL) 
               
               
                 Ipilimumab (Yervoy ®) 
                 Metastatic melanoma 
               
               
                 Bevacizumab (Avastin ®) 
                 Colon cancer, lung cancer, renal cancer, ovanan cancer, 
               
               
                   
                 glioblastoma multiforme 
               
               
                 Cetuximab (Erbitux ®) 
                 Colorectal cancer, non-small cell lung cancer, head and 
               
               
                   
                 neck cancer, cervical cancer, glioblastoma, ovarian 
               
               
                   
                 epithelia, fallopian tube or primary peritoneal cancer, 
               
               
                   
                 renal cell cancer 
               
               
                 Panitumumab (Vectibix ®) 
                 Colorectal cancer 
               
               
                 Trastuzumab (Herceptin ®) 
                 Breast cancer, Adenocarcinoma 
               
               
                   90 Y-ibritumomab 
                 Non-Hodgkin lymphoma 
               
               
                 tiuxetan (Zevalin ®) 
                   
               
               
                 Brentuximab vedotin 
                 Hodgkin lymphoma, Anaplastic large cell lymphoma 
               
               
                 (Adcetris ®) 
                   
               
               
                 Blinatumomab (Blincyto) 
                 Acute lymphocytic leukemia (ALL) 
               
               
                 Pembrolizumab (Keytruda ®) 
                 PD-1 (melanoma, non-small cell lung cancer) 
               
               
                 Nivolumab (Opdivo ®) 
                 PD-1 (melanoma, non-small cell lung cancer) 
               
               
                 Ofatumumab (Arzerra ®) 
                 Chronic lymphocytic leukemia (CLL) 
               
               
                 Pertuzumab (Perieta ®) 
                 Breast cancer 
               
               
                 Obinutuzumab (Gazyva ®) 
                 Lymphoma, diffuse large B-cell lymphoma (DLBCL), 
               
               
                   
                 indolent NEIL (1st-line) 
               
               
                 Din u tux imab (Unitux jn ®) 
                 Neuroblastoma 
               
               
                 Denosurnab (Prolia ®) 
                 Bone metastases, multiple myeloma, giant cell tumor 
               
               
                   
                 of bone 
               
               
                 RG6016 (LSD1 inhibitor) mAB 
                 Acute myelogenous leukemia (AML) 
               
               
                 Small molecule according to 
                   
               
               
                 BioCentury BCIQ 
                   
               
               
                 RG7882 (antibody drug 
                 Pancreatic cancer, ovarian cancer 
               
               
                 conjugate) 
                   
               
               
                 Alternative Names: D-4064A; 
                   
               
               
                 DMUC 4064A; RG7882 
                   
               
               
                 Lifastuzumab vedotin (antibody 
                 Platinum-resistant ovarian cancer, NSCLC 
               
               
                 drug conjugate) 
                   
               
               
                 Polatuzumab vedotin (antibody 
                 DLBCL, NHL 
               
               
                 drug conjugate) 
                   
               
               
                 RG7446 (anti-PD-L1 mAb) 
                 bladder cancer, NSCLC, melanoma, breast, renal cell 
               
               
                   
                 carcinoma, lymphoma 
               
               
                 Atezolizumab (Tecentriq ®, 
                 Bladder cancer, metastatic NSCLC 
               
               
                 anti-PD-L1) 
                   
               
               
                 DLYE-5953A (anti-Ly6E mAB 
                 Refractory solid tumors 
               
               
                 cytotoxic drug conjugate) 
                   
               
               
                 Duligotuzumab 
                 Solid tumors with mutant KRAS 
               
               
                 (anti-HER3/EGFR DAF mAb) 
                   
               
               
                 RG7117 (ERBB-3 receptor 
                 Metastatic breast cancer 
               
               
                 antagonist) 
                   
               
               
                 RG7155 (CSF-1R antagonist) 
                 Solid tumors 
               
               
                 RG-7450 (anti-STEAP1 antibody 
                 Prostate cancer 
               
               
                 drug conjugate) 
                   
               
               
                 RG7802 (CD3/CEA bispecific 
                 Solid tumors 
               
               
                 antibody) 
                   
               
               
                 RG7813 (CEA inhibitor) 
                 Solid tumors 
               
               
                 RG7841 (antibody drug 
                 Solid tumors 
               
               
                 conjugate) 
                   
               
               
                 RG7876 (CD40 antigen 
                 Solid tumors 
               
               
                 stimulant) 
                   
               
               
                 RG7888 (anti-OX40 mAb) 
                 Solid tumors 
               
               
                 RG7221 (Ang2-VEGF mAb) 
                 Metastatic colorectal cancer 
               
               
                 RG7686 (glypican-3 mAb) 
                 Hepatocellular carcinoma 
               
               
                 Perjeta ® pertuzumab 
                 HER3-positive breast cancer, gastric cancer 
               
               
                 Avelumab (anti-PD-L1 mAb) 
                 Solid tumor, gastric cancer, Merkel cell carcinoma, 
               
               
                   
                 non-small cell lung cancer 
               
               
                 Durvalumab (anti-PD-L1 mAb) 
                 NSCLC, head and neck, bladder, gastric, pancreatic, 
               
               
                   
                 HCC and blood cancers 
               
               
                 Pidilizumab/CT-011 
                 Lymphoma, myeloma 
               
               
                 (anti-PD-1 mAb) 
                   
               
               
                 BMS 936559/MDX-1105 
                 melanoma, non-small cell lung cancer 
               
               
                 (anti-PD-L1 mAb) 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the at least one therapeutic agent is selected from ahiraterone, bendamustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everolimus, gefitinib, idarubicin, imatinib, hydroxyurea, imatinib, lapatinib, leuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, sorafenib, vernurafenib, sunitinib, teniposide, triplatin, vinblastine, vinorelbine, vincristine, and cyclophosphamide. 
     Table 2 depicts a list of non-limiting list of cancer therapeutic agents. In one embodiment, the therapeutic agent is selected from the agents recited in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Cancer therapeutic agents 
               
               
                 Cancer Drugs 
               
            
           
           
               
               
            
               
                 Drug 
                 Target(s) 
               
               
                   
               
               
                 Abitrexate (Methotrexate) 
                 Acute lymphoblastic leukemia; breast cancer; 
               
               
                   
                 gestational trophoblastic disease, head and 
               
               
                   
                 neck cancer; lung cancer; mycosis fungoides 
               
               
                   
                 non-Hodgkin lymphoma; osteosarcoma 
               
               
                 Ado-Trastuzumab Emtansine 
                 Breast cancer 
               
               
                 Adriamycin (Doxorubicin Hydrochloride) 
                 Acute lymphoblastic leukemia; acute myeloid 
               
               
                   
                 leukemia; breast cancer, gastric (stomach) 
               
               
                   
                 cancer; Hodgkin lymphoma neuroblastoma; 
               
               
                   
                 non-Hodgkin lymphoma; ovarian cancer; small 
               
               
                   
                 cell lung cancer; soft tissue and bone sarcomas; 
               
               
                   
                 thyroid cancer; transitional cell bladder cancer; 
               
               
                   
                 Wilms tumor 
               
               
                 Adrucil, Efudex, Fluoroplex (Fluoromacil) 
                 Basal cell carcinoma; breast cancer; colorectal 
               
               
                   
                 cancer; gastric (stomach) adenocarcinoma; 
               
               
                   
                 pancreatic cancer; squamous cell carcinoma of 
               
               
                   
                 the head and neck 
               
               
                 Afinitor (Everolimus) 
                 Breast cancer, pancreatic cancer; renal cell 
               
               
                   
                 carcinoma; subependymal giant cell 
               
               
                   
                 astrocytoma 
               
               
                 Alimta (Pemetrexed Disodium) 
                 Malignant pleural mesothelioma; non-small 
               
               
                   
                 cell lung cancer 
               
               
                 Ambochlorin, Leukeran, or Linfolizin 
                 Chronic lymphocytic leukemia; Hodgkin 
               
               
                 (Chlorambucil) 
                 lymphoma; non-Hodgkin lymphoma 
               
               
                 Aredia (Pamidronate Disodium) 
                 Breast cancer; multiple myclotna. 
               
               
                 Arimidex (Anastrozole) 
                 Breast cancer 
               
               
                 Aromasin (Exemestane) 
                 Advanced breast cancer; early-stage breast 
               
               
                   
                 cancer and estrogen receptor positive 
               
               
                 Arranon (Nelarabine) 
                 T-cell acute lymphoblastic leukemia; T-cell 
               
               
                   
                 lymphoblastic lymphoma 
               
               
                 BEACOPP 
                 Hodgkin lymphoma 
               
               
                 Becenum, BiCNU (Carmustine) 
                 Brain tumors; Hodgkin lymphoma; multiple 
               
               
                   
                 myeloma; non-Hodgkin lymphoma 
               
               
                 Beleodaq (Belinostat) 
                 Peripheral T-cell lymphoma 
               
               
                 BEP 
                 Ovarian germ cell tumors; 
               
               
                   
                 testicular germ cell tumors 
               
               
                 Bleomycin 
                 Hodgkin lymphoma; non-Hodgkin lymphoma; 
               
               
                   
                 penile cancer; squamous cell carcinoma of the 
               
               
                   
                 cervix; squamous cell carcinoma of the head 
               
               
                   
                 and neck; squamous cell carcinoma of the 
               
               
                   
                 vulva; testicular cancer 
               
               
                 Bosulif (Bosutinib) 
                 Chronic myelogenous leukemia 
               
               
                 Busulfex or Myleran (Busulfan) 
                 Chronic myelogenous leukemia 
               
               
                 CAF 
                 Breast cancer 
               
               
                 Camptosar (Irinotecan Hydrochloride) 
                 Colorectal cancer 
               
               
                 CAPOX 
                 Colorectal cancer 
               
               
                 Casodex (Bicalutamide) 
                 Prostate cancer 
               
               
                 CccNU (Lomustine) 
                 Brain tumors; Hodgkin lymphoma 
               
               
                 Ceritinib 
                 Non-small cell lung cancer 
               
               
                 CHOP 
                 Non-Hodgkin lymphoma 
               
               
                 Clofarex (Clofarabine) 
                 Acute lymphoblastic leukemia 
               
               
                 CMF 
                 Breast cancer 
               
               
                 Cometriq (Cabozantinib-S-Malate) 
                 Medullary thyroid cancer 
               
               
                 COPP 
                 Hodgkin lymphoma; non-Hodgkin lymphoma 
               
               
                 COPP-ABV 
                 Hodgkin lymphoma 
               
               
                 Cosmegen (Dactinomycin) 
                 Ewing sarcoma; gestational trophoblastic 
               
               
                   
                 disease; rhabdomyosarcoma; solid 
               
               
                   
                 tumors; testicular cancer; Wilms tumor 
               
               
                 CVP 
                 Non-Hodgkin lymphoma; chronic 
               
               
                   
                 lymphocytic leukemia 
               
               
                 Cyfos (Ifosfamide) 
                 Testicular germ cell tumors 
               
               
                 Cytoxan or Neosar (Cyclophosphamide) 
                 Acute lymphoblastic leukemia; acute myeloid 
               
               
                   
                 leukemia; breast cancer; chronic lymphocytic 
               
               
                   
                 leukemia; chronic myelogenous leukemia; 
               
               
                   
                 Hodgkin lymphoma; multiple myeloma; 
               
               
                   
                 mycosis fungoides; neuroblastoma; non- 
               
               
                   
                 Hodgkin lymphoma; ovarian cancer; 
               
               
                   
                 retinoblastoma 
               
               
                 Dacarbazine 
                 Hodgkin lymphoma; melanoma 
               
               
                 Dacogen (Decitabine) 
                 Myelodysplastic syndromes 
               
               
                 Degarelix 
                 Prostate cancer 
               
               
                 Denileukin Diftitox 
                 Cutaneous T-cell lymphoma 
               
               
                 Denosumab 
                 Giant cell tumor of the bone; breast cancer, 
               
               
                   
                 prostate cancer 
               
               
                 DepoCyt ar DepoFoam (Liposomal Cytarabine) 
                 Lymphomatous meningitis 
               
               
                 DTIC-Dome (Dacarbazine) 
                 Hodgkin lymphoma; melanoma 
               
               
                 Ellence (Epirubicin Hydrochloride) 
                 Breast cancer 
               
               
                 Eloxatin (Oxaliplatin) 
                 Colorectal cancer; stage III colon cancer 
               
               
                 Emend (Aprepitant) 
                 Nausea and vomiting caused by chemotherapy 
               
               
                   
                 and nausea and vomiting after surgery 
               
               
                 EPOCH 
                 Non-Hodgkin lymphoma 
               
               
                 Erbitux (Cetuximab) 
                 Colorectal cancer; squamous cell carcinoma 
               
               
                   
                 of the head and neck 
               
               
                 Eribulin Mesylate 
                 Breast cancer 
               
               
                 Erivedge (Vismodegib) 
                 Basal cell carcinoma 
               
               
                 Erlotinib Hydrochloride 
                 Non-small cell lung cancer; pancreatic cancer 
               
               
                 Erwinaze (Asparaginase 
                 Acute lymphoblastic leukemia 
               
               
                 Erwinia chrysanthemi) 
                   
               
               
                 Etopophos (Etoposide Phosphate) 
                 Small cell lung cancer; testicular cancer 
               
               
                 Evacet or LipoDox or Doxil 
                 AIDS-related Kaposi sarcoma; multiple 
               
               
                 (Doxorubicin Hydrochloride Liposome) 
                 myeloma; ovarian cancer 
               
               
                 Evista or Keoxifene (Raloxifene Hydrochloride) 
                 Breast cancer 
               
               
                 Fareston (Toremifene) 
                 Breast cancer 
               
               
                 Farydak (Panobinostat) 
                 Multiple myeloma 
               
               
                 Faslodex (Fulvestrant) 
                 Breast cancer 
               
               
                 FEC 
                 Breast cancer 
               
               
                 Femara (Letrozole) 
                 Breast cancer 
               
               
                 Filgrastim 
                 Neutropenia 
               
               
                 Fludara (Fludambine Phosphate) 
                 Chronic lymphocytic leukemia 
               
               
                 FOLFIRI 
                 Colorectal cancer 
               
               
                 FOLFIRI-BEVACIZUMAB 
                 Colorectal cancer 
               
               
                 FOLFIRI-CETUXIMAB 
                 Colorectal cancer 
               
               
                 FOLFIRINOX 
                 Pancreatic cancer 
               
               
                 FOLFOX 
                 Colorectal cancer 
               
               
                 Folotyn (Pralatrexate) 
                 Peripheral T-cell lymphoma 
               
               
                 FU-LV 
                 Colorectal cancer; esophageal cancer; 
               
               
                   
                 gastric cancer 
               
               
                 GEMCITABINE-CISPLATIN 
                 Biliary tract cancer; bladder cancer; cervical 
               
               
                   
                 cancer; malignant mesothelioma; non-small 
               
               
                   
                 cell lung cancer; ovarian cancer; 
               
               
                   
                 pancreatic cancer 
               
               
                 GEMCITABINE-OXALIPLATIN 
                 Pancreatic cancer 
               
               
                 Gemzar (Gemcitabine Hydrochloride) 
                 Breast cancer; non-small cell lung cancer; 
               
               
                   
                 ovarian cancer; pancreatic cancer 
               
               
                 Gilotrif (Afatinib Dimaleate) 
                 Non-small cell lung cancer 
               
               
                 Gleevcc (Imatinib Mesylate) 
                 Acute lymphoblastic leukemia; chronic 
               
               
                   
                 eosinophilic leukemia or hypereosinophilic 
               
               
                   
                 syndrome; chronic myelogenous leukemia; 
               
               
                   
                 dermatofibrosarcoma protuberans; 
               
               
                   
                 gastrointestinal stromal tumor; 
               
               
                   
                 myelodysplastic/myeloproliferative neoplasms; 
               
               
                   
                 systemic mastocytosis. 
               
               
                 Gliadel (Carmustine Implant) 
                 Glioblastoma multiforme; malignant glioma 
               
               
                 Halaven (Eribulin Mesylate) 
                 Breast cancer 
               
               
                 Hycamtin (Topotecan Hydrochloride) 
                 Cervical cancer; ovarian cancer; 
               
               
                   
                 small cell lung cancer 
               
               
                 Hyper-CVAD 
                 Acute lymphoblastic leukemia; non-Hodgkin 
               
               
                   
                 lymphoma 
               
               
                 Ibrance (Palbociclib) 
                 Breast cancer 
               
               
                 ICE 
                 Hodgkin lymphoma: non-Hodgkin lymphoma 
               
               
                 Iclusig (Ponatinib Hydrochloride) 
                 Acute lymphoblastic leukemia, Chronic 
               
               
                   
                 myelogenous leukemia 
               
               
                 Idamycin (Idarubicin Hydrochloride) 
                 Acute myeloid leukemia 
               
               
                 Imbruvica (Ibruitinib) 
                 Chronic lymphocytic, leukemia; mantle cell 
               
               
                   
                 lymphoma; Waldenstr6m macroglobulinemia 
               
               
                 Inlyta (Axitinib) 
                 Renal cell carcinoma 
               
               
                 Iressa (Gefitinib) 
                 Non-small cell lung cancer 
               
               
                 Istodax (Romidepsin) 
                 Cutaneous T-cell lymphoma 
               
               
                 Ixempra (Ixabepilone) 
                 Breast cancer 
               
               
                 Jevtana (Cabazitaxel) 
                 Prostate cancer 
               
               
                 Kyprolis (Carfilzomib) 
                 Multiple myeloma 
               
               
                 Lenvima (Lenvatinib Mesylate) 
                 Thyroid cancer 
               
               
                 Leuprolide Acetate 
                 Prostate cancer 
               
               
                 Lupron (Leuprolide Acetate) 
                 Prostate cancer 
               
               
                 Lynparza (Olaparib) 
                 Ovarian cancer 
               
               
                 Marqibo (Vincristine Sulfate Liposome) 
                 Acute lymphoblastic leukemia 
               
               
                 Matulane (Procarbazine Hydrochloride) 
                 Hodgkin lymphoma 
               
               
                 Megace (Megestrol Acetate) 
                 Breast cancer; endometrial cancer 
               
               
                 Mekinist (Trametinib) 
                 Melanoma 
               
               
                 Mesnex (Mesna) 
                 Hemorrhagic cystitis 
               
               
                 Mitoxantrone Hydrochloride 
                 Acute myeloid leukemia; prostate cancer 
               
               
                 Mitozytrex (Mitomycin C) 
                 Gastric (stomach) and 
               
               
                   
                 pancreatic adenocarcinoma 
               
               
                 MOPP 
                 Hodgkin lymphoma 
               
               
                 Mozobil (Plerixafor) 
                 Multiple myeloma; non-Hodgkin lymphoma 
               
               
                 Mustargen 
                 Bronchogenic carcinoma, chronic lymphocytic 
               
               
                 (Mechlorethamine Hydrochloride) 
                 leukemia; chronic myelogenous leukemia; 
               
               
                   
                 Hodgkin lymphoma; malignant pleural 
               
               
                   
                 effusion, malignant pericardial effusion, and 
               
               
                   
                 malignant peritoneal effusion; mycosis 
               
               
                   
                 fungoides; non-Hodgkin lymphoma 
               
               
                 Mylotarg (Gemtuzumab Ozogamicin) 
                 Acute myeloid leukemia 
               
               
                 Navelbine (Vinorelbine Tartrate) 
                 Non-small cell lung cancer 
               
               
                 Nexavar (Sorafenib Tosylate) 
                 Hepatocellular carcinoma; Renal cell 
               
               
                   
                 carcinoma; Thyroid cancer 
               
               
                 Nilotinib 
                 Chronic myelogenous leukemia 
               
               
                 Nolvadex (Tamoxifen Citrate) 
                 Breast cancer 
               
               
                 Odomzo (Sonidegib) 
                 Basal cell carcinoma 
               
               
                 OEPA 
                 Hodgkin lymphoma 
               
               
                 OFF 
                 Pancreatic cancer 
               
               
                 Oncaspar (Pegaspargase) 
                 Acute lymphoblastic leukemia 
               
               
                 OPPA 
                 Hodgkin lymphoma 
               
               
                 Paclitaxel 
                 AIDS-related Kaposi sarcoma; Breast cancer; 
               
               
                   
                 Non-small cell lung cancer; Ovarian cancer 
               
               
                 PAD 
                 Multiple myeloma 
               
               
                 Paraplat (Carboplatin) 
                 Non-small cell lung cancer; Ovarian cancer 
               
               
                 Paraplatin (Carboplatin) 
                 Non-small cell lung cancer; Ovarian cancer 
               
               
                 Platinol (Cisplatin) 
                 Bladder cancer; Cervical cancer; Malignant 
               
               
                   
                 mesothelioma; Non-small cell lung cancer; 
               
               
                   
                 Ovarian cancer; Squamous cell carcinoma of 
               
               
                   
                 the head and neck; Testicular cancer 
               
               
                 Pomalyst (Pomalidomide) 
                 Multiple myeloma 
               
               
                 Pontinib Hydrochloride 
                 Acute lymphoblastic leukemia; Chronic 
               
               
                   
                 myelogenous leukemia 
               
               
                 Prednisone 
                 Acute lymphoblastic leukemia; Chronic 
               
               
                   
                 lymphocytic leukemia; Hodgkin lymphoma; 
               
               
                   
                 Multiple myeloma; Non-Hodgkin lymphoma; 
               
               
                   
                 Prostate cancer; Thymoma and thymic 
               
               
                   
                 carcmoma 
               
               
                 Provenge (Sipuleucel-T) 
                 Prostate cancer 
               
               
                 Purinethol (Mercaptopurine) 
                 Acute lymphoblastic leukemia 
               
               
                 Radium 223 Dichloride 
                 Prostate cancer 
               
               
                 R-CHOP 
                 Non-Hodgkin lymphoma 
               
               
                 R-CVP 
                 Non-Hodgkin lymphoma 
               
               
                 R-EPOCH 
                 B-cell on-Hodgkin lymphoma 
               
               
                 Revlimid (Lenalidomide) 
                 Mantle cell lymphoma; Multiple myeloma; 
               
               
                   
                 Anemia 
               
               
                 Rubidomycin (Daunorubicin Hydrochloride) 
                 Acute lymphoblastic leukemia; 
               
               
                   
                 Acute myeloid leukemia 
               
               
                 Sipuleucel-T 
                 Prostate cancer 
               
               
                 Somatuline Depot (Lanreotide Acetate) 
                 Gastroenteropancreatic neuroendocrine tumors 
               
               
                 Sprycel (Dasatinib) 
                 Acute lymphoblastic leukemia; Chronic 
               
               
                   
                 myelogenous leukemia. 
               
               
                 STANFORD V 
                 Hodgkin lymphoma 
               
               
                 Stivarga (Regorafenib) 
                 Colorectal cancer; Gastrointestinal 
               
               
                   
                 stromal tumor 
               
               
                 Sutent (Sunitinib Malate) 
                 Gastronintestinal stromal tumor; Pancreatic 
               
               
                   
                 cancer; Renal cell carcinoma 
               
               
                 Synovir (Thalidomide) 
                 Multiple myeloma 
               
               
                 Synribo (Omacetaxine Mepesuccinate) 
                 Chronic myelogenous leukemia 
               
               
                 TAC 
                 Breast cancer 
               
               
                 Tafinlar (Dabrafenib) 
                 Melanoma 
               
               
                 Tarabine PFS (Cytarabine) 
                 Acute lymphoblastic leukemia; Acute myeloid 
               
               
                   
                 leukemia; Chronic myelogenous leukemia; 
               
               
                   
                 meningeal leukemia 
               
               
                 Tarceva (Erlotinib Hydrochloride) 
                 Non-small cell lung cancer; Pancreatic cancer 
               
               
                 Targretin (Bexarotene) 
                 Skin problems caused by cutaneous 
               
               
                   
                 T-cell lymphoma 
               
               
                 Tasigna (Niltinib) 
                 Chronic myelogenous leukemia 
               
               
                 Taxol (Paclitaxel) 
                 AIDS-related Kaposi sarcoma; Breast cancer; 
               
               
                   
                 Non-small cell lung cancer; Ovarian cancer 
               
               
                 Taxotere (Docetaxel) 
                 Breast cancer; Adenocarcinoma; Non-small 
               
               
                   
                 cell lung cancer; Prostate cancer; Squamous 
               
               
                   
                 cell carcinoma of the head and neck; 
               
               
                   
                 adenocarcinoma of the stomach or 
               
               
                   
                 gastroesophageal junction; 
               
               
                 Temodar or Methazolastone 
                 Anaplastic astrocytoma; 
               
               
                 (Temozolomide) 
                 Glioblastoma multiforme 
               
               
                 Thiotepa 
                 Bladder cancer; Breast cancer; Malignant 
               
               
                   
                 pleural effusion, malignant pericardial 
               
               
                   
                 effusion, and malignant peritoneal effusion; 
               
               
                   
                 Ovarian cancer 
               
               
                 Toposar or VePesid (Etoposide) 
                 Small cell lung cancer; Testicular cancer 
               
               
                 Torisel (Temsirolimus) 
                 Renal cell carcinoma 
               
               
                 TPF 
                 Squamous cell carcinoma of the head and 
               
               
                   
                 neck; Gastric (stomach) cancer 
               
               
                 Treanda (Bendamustine Hydrochloride) 
                 B-cell non-Hodgkin lymphoma; Chronic 
               
               
                   
                 lymphocytic leukemia 
               
               
                 Trisenox (Arsenic Trioxide) 
                 Acute promyelocytic leukemia 
               
               
                 Tykerb (Lapatinib Ditosylate) 
                 Breast cancer 
               
               
                 Vandetabib 
                 Medullary thyroid cancer 
               
               
                 VAMP 
                 Hodgkin lymphoma 
               
               
                 VeIP 
                 Ovarian germ cell; Testicular cancer 
               
               
                 Velcade (Bortezomib) 
                 Mulitple myeloma; Mantle cell lymphoma 
               
               
                 Velsar or Velban (Vinblastine Sulfate) 
                 Breast cancer; Choriocarcinoma; Hodgkin 
               
               
                   
                 lymphoma; Kaposi sarcoma; Mycosis 
               
               
                   
                 fungoides; Non-Hodgkin lymphoina; 
               
               
                   
                 Testicular cancer 
               
               
                 Viadur Leuprolide Acetate) 
                 Prostate cancer 
               
               
                 Vidaza (Azacitidine) 
                 Myelodysplastic syndromes 
               
               
                 Vincasar PFS (Vincristine Sulfate) 
                 Acute leukemia; Hodgkin lymphoma; 
               
               
                   
                 Neuroblastoma; Non-Hodgkin lymphoma; 
               
               
                   
                 Rhabdomyosarcoma; Wilms tumor 
               
               
                 VIP 
                 Testicular cancer 
               
               
                 Visbodegib 
                 Basal cell carcinoma 
               
               
                 Votrient (Pazopanib Hydrochloride) 
                 Renal cell carcinoma; Soft tissue sarcoma 
               
               
                 Wellcovorin (Leucovorin Calcium) 
                 Colorectal cancer; Anemia 
               
               
                 Xalkori (Crizotinib) 
                 Non-small cell lung cancer 
               
               
                 Xeloda (Capecitabine) 
                 Breast cancer; Colorectal cancer 
               
               
                 XELIRI 
                 Colorectal cancer; Esophageal cancer; 
               
               
                   
                 Gastric (stomach) cancer 
               
               
                 XELOX 
                 Colorectal cancer 
               
               
                 Xofigo (Radium 223 Dichloride) 
                 Prostate cancer 
               
               
                 Xtandi (Enzalutamide) 
                 Prostate cancer 
               
               
                 Zaltrap (Ziv-Afibercept) 
                 Colorectal cancer 
               
               
                 Zelboraf (Vemurafenib) 
                 Melanoma 
               
               
                 Zoladex (Goserelin Acetate) 
                 Breast cancer; Prostate cancer 
               
               
                 Zolinza (Vorinostat) 
                 Cutaneous T-cell lymphoma 
               
               
                 Zometa (Zoledronic Acid) 
                 Multiple myeloma 
               
               
                 Zydelig (Idelalisib) 
                 Chronic lymphocytic leukemia; Non-Hodgkin 
               
               
                   
                 lymphoma (Follicula B-cell non Hodgkin 
               
               
                   
                 lymphoma and Small lymphocytic lymphoma) 
               
               
                 Zykadia (Certinib) 
                 Non-small cell lung cancer 
               
               
                 Zytiga (Abiraterone Acetate) 
                 Prostate cancer 
               
               
                   
               
            
           
         
       
     
     It is to be understood that the therapeutic agent may be located inside the nanoparticle, on the outside surface of the nanoparticle, or both. The nanoparticle may contain more than one therapeutic agent, for example, two therapeutic agents, three therapeutic agents, four therapeutic agents, five therapeutic agents, or more. Furthermore, a nanoparticle may contain the same or different therapeutic agents inside and outside the nanoparticle. 
     In one aspect, the nanoparticle comprises at least 100 binding agents non-covalently bound to the surface of the nanoparticle. In one aspect, the nanoparticle comprises at least 200, 300, 400, 500, 600, 700 or 800 binding agents non-covalently bound to the surface of the nanoparticle. 
     In one aspect, the nanoparticle comprises between about 100 and about 1000 binding agents non-covalently bound to the surface of the nanoparticle. In one aspect, the nanoparticle comprises between about 200 and about 1000, between about 300 and about 1000, between about 400 and about 1000, between about 500 and about 1000, between about 600 and about 1000, between about 200 and about 800, between about 300 and about 800, or between about 400 and about 800 binding agents non-covalently bound to the surface of the nanoparticle. Contemplated values include any value or subrange within any of the recited ranges, including endpoints. 
     In one aspect, the average particle size in the nanoparticle composition is less than about 1 μm. In one aspect, the average particle size in the nanoparticle composition is between about 50 nm and about 1 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 900 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 800 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 700 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 600 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 500 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 400 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 300 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 200 nm. In one aspect, the average particle size in the nanoparticle composition is between about 80 nm and about 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 mn, 300 nm, or 200 nm. In one aspect, the average particle size in the nanoparticle composition is between about 100 nm and about 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. In one aspect, the average particle size in the nanoparticle composition is between about 120 nm and about 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints. 
     In one aspect, the nanoparticle composition is formulated for intravenous injection. In order to avoid an ischemic event, the nanoparticle composition formulated for intravenous injection should comprise nanoparticles with an average particle size of less than about 1 μm. 
     In one aspect, the average particle size in the nanoparticle composition is greater than about 1 μm. In one aspect, the average particle size in the nanoparticle composition is between about 1 μm and about 5 μm, between about 1 μm and about 4 μm, between about 1 pm and about 3 μm, between about 1 μm and about 2 nm, or between about 1 μm and about 1.5 μm. Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints. 
     In one aspect, the nanoparticle composition is formulated for direct injection into a tumor. Direct injection includes injection into or proximal to a tumor site, perfusion into a tumor, and the like. When formulated for direct injection into a tumor, the nanoparticle may comprise any average particle size. Without being bound by theory, it is believed that larger particles (e.g., greater than 500 nm, greater than 1 μm, and the like) are more likely to be immobilized within the tumor, thereby providing a beneficial effect. Larger particles can accumulate in the tumor or specific organs. See, e.g., 20-60 micron glass particle that is used to inject into the hepatic artery feeding a tumor of the liver called “THERASPHERE®” (in clinical use for liver cancer). Therefore, for intravenous administration, particles under 1 μm are typically used. Particles over 1 μm are, more typically, administered directly into a tumor (“direct injection”) or into an artery feeding into the site of the tumor. 
     In one aspect, less than about 0.01% of the nanoparticles within the composition have a particle size greater than 200 nm, greater than 300 nm, greater than 400 nm, greater than 500 nm, greater than 600 nm, greater than 700 nm, or greater than 800 nm. In one aspect, less than about 0.001% of the nanoparticles within the composition have a particle size greater than 200 nm, greater than 300 nm, greater than 400 nm, greater than 500 nm, greater than 600 nm, greater than 700 nm, or greater than 800 nm. In a preferred embodiment, less than about 0.01% of the nanoparticles within the composition have a particle size greater than 800 nm. In a more preferred embodiment, less than about 0.001% of the nanoparticles within the composition have a particle size greater than 800 nm. 
     In a preferred aspect, the sizes and size ranges recited herein relate to particle sizes of the reconstituted lyophilized nanoparticle composition. That is, after the lyophilized nanoparticles are resuspended in an aqueous solution (e.g., water, other pharmaceutically acceptable excipient, buffer, etc.), the particle size or average particle size is within the range recited herein. 
     In one aspect, at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%. 97%., 98%, 99%, 99.5%, or 99.9% of the, nanoparticles are present in the reconstituted composition as single nanoparticles. That is, fewer than about 50%, 40%, 30%, etc. of the nanoparticles are dimerized or multimerized (otigomerized). 
     In some embodiments, the nanoparticles in the composition have less than 20% by number dimerization, less than 10% by number dimerization and preferably less than 5% dimerization. 
     In some embodiments, the size of the nanoparticle can be controlled by the adjusting the amount (e.g., ratio) of carrier protein to paclitaxel or paclitaxel derivative, and/or ratio of carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles to binding agent. The size of the nanoparticles, and the size distribution, is also important. The nanoparticles of the invention may behave differently according to their size. At large sizes, an agglomeration may block blood vessels. Therefore, agglomeration of nanoparticles can affect the performance and safety of the composition. On the other hand, larger particles may be more therapeutic under certain conditions (e.g., when not administered intravenously). 
     Further challenges are imposed because the nanoparticles are used in therapy. 
     While rearrangement of the components in the nanoparticle may be mitigated through covalent bonds between the components, such covalent bonds pose challenges for the therapeutic use of nanoparticles in cancer treatment. The binding agent, carrier protein, and therapeutic agent typically act at different locations in a tumor and through different mechanisms. Non-covalent bonds permit the components of the nanoparticle to dissociate at the tumor, Thus, while a covalent bond may be advantageous for lyophilization, it may he disadvantageous for therapeutic use. 
     The size of nanoparticles, and the distribution of the size, s also important. Nanoparticles may behave differently according to their size. At large sizes, nanoparticles or the agglomeration of the particles may block blood vessels either of which can affect the performance and safety of the composition. 
     Paclitaxel Derivatives 
     Paclitaxel derivatives used in the present invention preferably are less toxic than paclitaxel. That is, the paclitaxel derivative is less toxic to cells (e.g., does not kill cancer and/or normal cells as well as, or does not inhibit cell proliferation as well as) compared to paclitaxel. Paclitaxel derivatives may include any derivative or precursor of paclitaxel. Examples include, but are not limited to, 20-Acetoxy-4-deactyl-5-epi-20, O-secotaxol (the Meerwein Product of Paclitaxel), or Baccatin III ((2β, 5α, 7α, 10α, 13β)-4,10-Diacetoxy-1,7,13-trihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate). 
     For example, most of the C-13 simplified paclitaxel derivatives and derivatives of different stereochemistry demonstrated reduced activity in comparison to paclitaxel. The 2′-hydroxyl and the 3′-benzamido group are not essential for bioactivity, but are important for strong microtubule binding and cytotoxicity. Formation of ethers at 2′-hydroxyl group, such as alkyl ether (e.g., methyl ether) and alkyl silyl ether (e.g., ter-butyldimethylsilyl ether), reduced cytotoxicity. Acylation of the 2′-hydroxyl group (e.g., 2′-acetyltaxol) also leads to loss of activity. Replacement of 2′-hydroxyl group by halogen (e.g, fluorine) was also found to significantly reduce the cytotoxicity. Lead tetracetate oxidation of 6α-hydroxy-7-epi-paclitaxel leads to C-nor-paclitaxel and C-seco-paclitaxel derivatives. Tetrapropylammonium perruthenate (TPAP) oxidation of a 6α-hydroxy-7-epi-paclitaxel derivative leads to a 6-formyl-C-nor-paclitaxcel derivative. Reaction of a 6α-O-trifluoromethanesulfonyl-7-epi-paclitaxel derivative with DMAP yields a 20-O-acetyl-4-deacetyl-5,6-dehydro-6-formyl-C-nor-paclitaxel derivative. C-nor-paclitaxel analogs are less active than paclitaxel. Therefore, the paclitaxel derivative may include modifications at any one or more of these sites or produced by one or more of these methods. See, e.g., Liang et al.  Tetrahedron,  53(10):3441-3456 (1997); U.S. Pat. Nos. 5,756,301; and 5,981,777; each of which is incorporated by reference herein in its entirety. 
     Methods of Making Nahoparticles and Nanoparticle Complexes 
     In some aspects, the current invention relates to methods of making nanoparticle compositions as described herein. In some embodiments, this disclosure relates to methods of making the nanoparticle compositions, wherein said method comprises contacting the carrier protein and the paclitaxel or paclitaxel derivative under conditions and ratios of components that will allow for formation of the desired nanoparticles. In some embodiments, the methods further relate to contacting a nanoparticle with binding agents and/or therapeutic agent under conditions to form nanoparticle complexes. 
     In some embodiments, the nanoparticles are made by combining the carrier protein and paclitaxel or paclitaxel derivative, and homogenizing under high pressure to form stable nanoparticles. Non-limiting methods for homogenizing albumin and taxane paclitaxel) can be found, for example, in Example 1, as well as U.S. Pat. Nos. 5,916,596; 6,506,405; and 6,537,579, each of which is incorporated herein by reference in its entirety. 
     In one embodiment, binding agents and/or therapeutic agents are complexed to the nanoparticles as described, for example, in U.S. Pat. Nos. 9,757,453, and 9,446,148. 
     In some aspects, provided herein are methods of making nanoparticle complexes, wherein said methods comprise contacting the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticle with the binding agents and/or therapeutic agent in a solution haing a pH of between 5.0 and 7.5 and a temperature between about 5° C. and about 60° C., between about 23° C. and about 60° C., or between about 55° C. and about 60° C. under conditions and ratios of components that will allow for formation of the desired nanoparticles. In one embodiment, the nanoparticle is made at 55-60° C. and pH 7.0. In another aspect provided herein are methods of making the nanoparticle complexes, wherein said method comprises (a) homogenizing the carrier protein and paclitaxel (or paclitaxel derivative) to form a nanoparticle core; and (b) contacting the core with the antibodies in a solution having a pH of about 5.0 to about 7.5 at a temperature between about 5° C. and about 60° C., between about 23° C. and about 60° C., or between about 55° C. and about 60° C. under conditions and ratios of components that will allow for formation of the desired nanoparticle complexes. 
     Another embodiment of the invention includes a method for making a nanoparticle composition by facilitating complex formation of a protein carrier and a therapeutic agent, the method comprising contacting the carrier protein, an amount of paclitaxel as described herein, and a therapeutic agent in a solution having a pH of 5.0 or greater and a temperature between about 5° C. and about 60° C., to generate a nanoparticle. In yet another embodiment, the method further comprises contacting the protein-carrier complex with a binding agent. 
     The amount of components (e.g., carrier protein, antibodies, paclitaxel or paclitaxel derivative, therapeutic agents, combinations thereof) is controlled in order to provide for formation of the desired nanoparticles. A composition wherein the amount of components is too dilute will not form the nanoparticles as described herein. An overly concentrated solution will result in unstructured aggregates. 
     In a preferred embodiment, weight ratio of carrier protein to binding agent is 10:4. In some embodiments, the amount of carder protein is between about 1 mg/mL and about 100 mg/mL. In some embodiments, the amount of binding agent is between about 1 mg/mL and about 30 mg/mL. For example, in some embodiments, the ratio of carrier protein: binding agent: solution is approximately 9 mg of carrier protein (e.g., albumin) to 4 mg of binding agent (e.g., BEV) in 1 mL of solution (e.g., saline). 
     In one embodiment, the amount of solution or other liquid medium employed to form the nanoparticles is particularly important. In some embodiments, the amount of solution (e.g., sterile water, saline, phosphate buffered saline) employed is between about 0.5 mL of solution to about 20 mL of solution. 
     In one aspect, the nanoparticle complexes of the nanoparticle composition are formed by contacting the carrier protein-paclitaxel (opr paclitaxel derivative) nanoparticles and at least one therapeutic agent with the binding agent at a ratio of about 10:1 to about 10:30 carrier protein particle or carrier protein-therapeutic agent particle to binding agent. In one embodiment, the ratio is about 10:2 to about 10:25. In one embodiment, the ratio is about 10:2 to about 1:1. In a preferred embodiment, the ratio is about 10:2 to about 10:6. In an especially preferred embodiment, the ratio is about 10:4. Contemplated ratios include any value, subrange, or range within any of the recited ranges, including endpoints. 
     In one aspect, the nanoparticles of the nanoparticle composition are formed by contacting the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles and at least one therapeutic agent. In one embodiment, the ratio is about 10:2 to about 10:25. In one embodiment, the ratio is about 10:2 to about 1:1. In a preferred embodiment, the ratio is about 10:2 to about 10:6. In an especially preferred embodiment, the ratio is about 10:4. Contemplated ratios include any value, subrange, or range within any of the recited ranges, including endpoints. 
     In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH between about 4 and about 8. In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 4. In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 5. In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 6. In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 7. In one embodiment, the carrie carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 8. In a preferred embodiment, the carrier protein-pad itaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH between about 5 and about 7. 
     In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are incubated with the binding agent at a temperature of about 5° C. to about 60° C., or any range, subrange, or value within that range including endpoints. In a preferred embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are incubated with the binding agent at a temperature of about 23° C. to about 60° C. 
     Without being bound by theory, it is believed that the stability of the nanoparticle complexes is, at least in part, dependent upon the temperature and/or pH at which the nanoparticles are formed, as well as the concentration of the components carrier protein, binding agent, paclitaxel or paclitaxel derivative, and a therapeutic agent) in the solution. In one embodiment, the K d  of the nanoparticles is between about 1×10 −11  M and about 2×10 −5  M. In one embodiment, the K d  of the nanoparticles is between about 1×10 −11  M and about 2×10 −8  M. In one embodiment, the K d  of the nanoparticles is between about 1×10 −11  M and about 7×10 −9  M. In a preferred embodiment, the K d  of the nanoparticles is between about 1×10 −11  M and about 3×10 −8  M. Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints. 
     Making Reduced-Toxicity Nanoparticles 
     The relative weight ratio of the carrier protein to the paclitaxel is greater than about 9:1. In one embodiment, the earlier protein and the paclitaxel have a relative weight ratios of greater than about 10:1, or about 11:1, or about 12:1, or about 13:1, or about 14:1, or about 15:1, or about 16:1, or about 17:1, or about 18:1, or about 19:1, or about 20:1, or about 21:1, or about 22:1, or about 23:1, or about 24:1, or about 25:1, or about 26:1, or about 27:1, or about 28:1, or about 29:1, or about 30:1, in one embodiment, the weight ratio is between 10:1 and 100:1, between 10:1 and 50:1, between 10:1 and 40:1, between 10:1 and 30:1, between 10:1 and 20:1, or between 10:1 and 15:1. In one embodiment, the weight ratio is between 15:1 and 50:1. 15:1 and 50:1, between 15:1 and 40:1, between 15:1 and 30:1, or between 15:1 and 20:1. The weight ratio may be any value or subrange within the recited ranges, including endpoints. 
     In one embodiment, the amount of paclitaxel is equal to a minimum amount capable of providing stability to the nanoparticles. In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of providing affinity of the at least one therapeutic agent to the protein carrier. In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of facilitating complex formation of the at least one therapeutic agent and the protein carrier. For example, less than about I mg of taxol can be added 9 mg of carrier protein (10 mg carrier protein-therapeutic) and 4 mg of binding agent, e.g., antibody, Fc fusion molecule, or aptamer, in 1 ml of solution. 
     It is to be noted that, when using a typical i.v, bag, for example, with the solution of approximately 1 liter one would need to use 1000× the amount of carrier protein/carrier protein therapeutic agent and antibodies compared to that used in 1 mL. Thus, one cannot form the present nanoparticles in a standard i.v. bag. Furthermore, when the components are added to a standard i.v. bag in the therapeutic amounts of the present invention, the components do not self-assemble to form nanoparticles. 
     In one embodiment, the amount of paclitaxel present in the nanoparticle composition is less than about 5 mg/mL. In one embodiment, the amount of paclitaxel present in the nanoparticle composition is less than about 4.54 mg/mL, or about 4.16 mg/mL, or about 3.57 mg/mL, or about 3.33 mg/mL, or about 3.12 mg/mL, or about 2.94 mg/mL, or about 2.78 mg/mL, or about 2.63 mg/mL, or about 2.5 mg/mL, or about 2.38 mg/mL, or about 2.27 mg/mL, or about 2.17 mg/mL, or about 2.08 mg/mL, or about 2 mg mL, or about 1.92 mg/mL, or about 1.85 mg/mL, or about 1.78 mg/mL, or about 1.72 mg/mL, or about 1.67 mg/mL. In one embodiment, the amount. of paclitaxel present in the nanoparticle composition is greater than or equal to a minimum amount capable of providing stability to the nanoparticles. In one embodiment, the amount of paclitaxel present in the nanoparticle composition is greater than or equal to a minimum amount capable of providing affinity of the at least one therapeutic agent to the protein carrier. In one embodiment, the amount of paclitaxel present in the nanoparticle composition is greater than or equal to a minimum amount capable of facilitating complex formation of the at least one therapeutic agent and the protein carrier. 
     In one embodiment, the nanoparticle compositions described herein includes no binding agents. 
     Lyophilization 
     While protein compositions comprising a single source protein are commonly stored in lyophilized form where they exhibit significant shelf-life, such lyophilized compositions do not contain a self-assembled nanoparticle of two different proteins integrated together by hydrophobic-hydrophobic interactions. Moreover, the nanoparticle configuration wherein a majority of the binding portions of the binding agent are exposed on the surface of the nanoparticles lends itself to being susceptible to dislodgement or reconfiguration by conditions which otherwise would be considered benign. For example, during lyophilization, ionic charges on the proteins are dehydrated thereby exposing the underlying charges. Exposed charges allow for charge-charge interactions between the two proteins which can alter the binding affinity of each protein to the other. In addition, the concentration of the nanoparticles increases significantly as the solvent (e.g., water) is removed. Such increased concentrations of nanoparticles could lead to irreversible oligomerization. Oligomerization is a known property of proteins that reduces the biological properties of the oligomer as compared to the monomeric form and increases the size of the particle sometimes beyond 1 micron. 
     On the other hand, a stable form of a nanoparticle composition is required for clinical and/or commercial use where a shelf-life of at least 3 months is required and shelf-lives of greater than 6 months or 9 months are preferred. Such a stable composition must be readily available for intravenous injection, must retain its self-assembled form upon intravenous injection so as to direct the nanoparticle to the predetermined site in vivo, must have a maximum size of less than 1 micron so as to avoid any ischemic event when delivered into the blood stream, and finally must be compatible with the aqueous composition used for injection. 
     Lyophilization, or freeze-drying, removes water from a composition. In the process, the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment. An excipient may be included in pre-lyophilized formulations to enhance stability during the freeze-drying process and/or to improve stability of the lyophilized product upon storage. Pikal, M. Biopharm. 3(9)26-30 (1990) and Arakawa et al., Pharm. Res. 8(3): 285-291 (1991). 
     While proteins may be lyophilized, the process of lyophilization and reconstitution may affect the properties of the protein. Because proteins are larger and more complex than traditional organic and inorganic drugs (i.e. possessing multiple functional groups in addition to complex three-dimensional structures), the formulation of such proteins poses special problems. For a protein to remain biologically active, a formulation must preserve intact the conformational integrity of at least a core sequence of the protein&#39;s amino acids while at the same time protecting the protein&#39;s multiple functional groups from degradation. Degradation pathways for proteins can involve chemical instability (i.e. any process which involves modification of the protein by bond formation or cleavage resulting in a new chemical entity) or physical instability (i.e. changes in the higher order structure of the protein). Chemical instability can result from deamidation, racemization, hydrolysis, oxidation, beta elimination or disulfide exchange. Physical instability can result from denaturation, aggregation, precipitation or adsorption, for example. The three most common protein degradation pathways are protein aggregation, deamidation and oxidation. Cleland, et al., Critical Reviews in Therapeutic Drug Carrier Systems 10(4): 307-377 (1993). 
     Finally, cryoprotectants and agents that assist in the lyophilization process must be safe and tolerated for therapeutic use. 
     The lyophilized compositions of this invention are prepared by standard lyophilization techniques with or without the presence of stabilizers, buffers, etc. Surprisingly, these conditions do not alter the relatively fragile structure of the nanoparticles. Moreover, at best, these nanoparticles retain their size distribution upon lyophilization and, more importantly, can be reconstituted for in vivo administration (e.g., intravenous delivery) in substantially the same form and ratios as if freshly made. 
     In some embodiments, the nanoparticles RTP or NTP) are lyophilized. In some embodiments, the nanoparticle complexes (e.g., RTP or NTP with associated therapeutic agent and/or binding agents) are lyophilized. In some embodiments, upon reconstitution with an aqueous solution, an amount of the binding agents are arranged on a surface of the nanoparticles. In some einbodimetns, the nanoparticle complexes are capable of binding to an antigen. In some embodiments, the antibodies associated with the nanoparticle complexes remain capable of binding to the antigen. 
     Formulations 
     In one aspect, the nanoparticle composition is formulated for systemic delivery, e.g., intravenous administration. 
     In one aspect, the nanoparticle composition is formulated for direct injection into a tumor. Direct injection includes injection into or proximal to a tumor site, perfusion into a tumor, and the like. Because the nanoparticle composition is not administered systemically, a nanoparticle composition is formulated for direct injection into a tumor may comprise any average particle size. Without being bound by theory, it is believed that larger particles (e.g., greater than 500 nm, greater than 1 μm, and the like) are more likely to be immobilized within the tumor, thereby providing what is believed to be a better beneficial effect. 
     In another aspect, provided herein is a composition comprising a compound provided herein, and at least one pharmaceutically acceptable excipient. 
     In general, the compounds provided herein can be formulated for administration to a patient by any of the accepted modes of administration. Various formulations and drug delivery systems are available in the art. See, e.g., Gennaro, A. R., ed. (1995)  Remington&#39;s Pharmaceutical Sciences,  18th ed., Mack Publishing Co. 
     In general, compounds provided herein will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. 
     The compositions are comprised of, in general, a. compound of the present invention in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do riot adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. 
     Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Other suitable pharmaceutical excipients and their formulations are described in Remington.&#39;s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990). 
     The present compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. 
     Treatment Methods 
     The nanoparticle compositions as described herein are useful in treating cancer cells and/ or tumors in a mammal. In a preferred embodiment, the mammal is a human a human patient). Preferably, a lyophilized nanoparticle composition is reconstituted (suspended in an aqueous excipient) prior to administration. 
     In one aspect is provided a method for treating a cancer cell, the method comprising contacting the cell with an effective amount of nanoparticle composition as described herein to treat the cancer cell. Treatment of a cancer cell includes, without limitation, reduction in proliferation, killing the cell, preventing metastasis of the cell, and the like. 
     In one aspect is provided a method for treating a tumor in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a nanoparticle composition as described herein to treat the tumor. In one embodiment, where the nanoparticles include a binding agent comprising an antigen-binding domain, the method comprises selecting a patient having a cancer which expresses the antigen. In one embodiment, the size of the tumor is reduced. In one embodiment, the tumor size does not increase (i.e. progress) for at least a period of time during and/or after treatment. 
     In one embodiment, the nanoparticle composition is administered intravenously. In one embodiment, the n.anoparticle composition is administered directly to the tumor. In one embodiment, the nanoparticle composition is administered by direct injection or perfusion into the tumor. 
     In one embodiment, the method comprises:
         a) administering the nanoparticle composition once a week for three weeks;   b) ceasing administration of the nanoparticle composition for one week; and   c) optionally repeating steps a) and b) as necessary to treat the tumor.       

     In one embodiment, the therapeutically effective amount of the nanoparticles described herein comprises about 1 mg/m 2  to about 200 mg/m 2  antibody, about 2 mg/m 2  to about 150 mg/m 2 , about 5 mg/m 2  to about 100 mg/m 2 , about 10 mg/m 2  to about 85 mg/m 2 , about 15 mg/m 2  to about 75 mg/m 2 , about 20 mg/m 2  to about 65 mg/m 2 , about 25 mg/m 2  to about 55 mg/m 2 , about 30 mg/m 2  to about 45 mg/m 2 , or about 35 mg/m 2  to about 40 mg/m 2  antibody. In other embodiments, the therapeutically effective amount comprises about 20 mg/m 2  to about 90 mg/m 2  antibody. In one embodiment, the therapeutically effective amount comprises 30 mg/m 2  to about 70 mg/m 2  antibody. 
     In one embodiment, the therapeutically effective amount of the nanoparticles described herein comprises about 50 mg/m 2  to about 200 mg/mn 2  carrier protein or carrier protein and therapeutic agent. In one embodiment, the therapeutically effective amount of the nanoparticle compositions described herein comprise no binding agents. In one embodiment, the therapeutically effective amount of the nanoparticle compositions described herein comprise less than about a therapeutically effective amount of paclitaxel. In a preferred embodiment, the therapeutically effective amount comprises about less than 75 mg/m 2  of paclitaxel. Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints. 
     In one embodiment, the therapeutically effective amount comprises about 20 mg/m 2  to about 90 mg/m 2  binding agent, e.g., antibody, aptamer or fusion protein. In a preferred embodiment, the therapeutically effective amount comprises 30 mg/m 2  to about 70 mg/m 2  binding agent, e.g., antibody, aptamer or fusion protein. Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints. 
     Cancers or tumors that can be treated by the compositions and methods described herein include, but are not limited to the cancers referred to in the above tables, as well as: biliary tract cancer, brain cancer, including glioblastomas and medulloblastomas; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer, gastric cancer; hematological neoplasms, including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms, including Bowen&#39;s disease and Paget&#39;s disease; liver cancer (hepatocarcinoma); lung cancer; lymphoma.s., including Hodgkin&#39;s disease and lymphocytic lymphomas; neuroblastomas; oral cancer, including squamous cell carcinoma; ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreas cancer; prostate cancer; rectal cancer; sarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma. and osteosarcoma; skin cancer, including melanoma, Kaposi&#39;s sarcoma, basocellular cancer and squamous cell cancer; testicular cancer, including germinal tumors (serninorna, non-seminomatteratomas, choriocarcinomas), stromal tumors and germ cell tumors; thyroid cancer, including thyroid adenocarcinoma and medullar carcinoma; and renal cancer including adenocarcinoma and Wilms tumor. In important embodiments, cancers or tumors include breast cancer, lymphoma, multiple myelorna, and melanoma. 
     In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the nanoparticles, depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well known to the skilled artisan. 
     An effective amount of such agents can readily be determined by routine experimentation, as can the most effective and convenient route of administration, and the most appropriate formulation. Various formulations and drug delivery systems are available in the art. See, e.g., Gennaro, A. R., ed. (1995)  Remington&#39;s Pharmaeutical Sciences,  18th ed., Mack Publishing Co. 
     An effective amount or a therapeutically effective amount or dose of an agent, e.g., a compound of the invention, refers to that amount of the agent or compound that results in amelioration of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50/ED50. Agents that exhibit high therapeutic indices are preferred. 
     The effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject&#39;s condition. 
     Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to achieve the desired effects; i.e., the minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. 
     In related embodiments, the treatment comprises administration of the targeting binding agent prior to administration of the nanoparticles. In one embodiment, the targeting binding agent is administered between about 6 and 48, or 12 and 48 hours prior to administration of the nanoparticles. In another embodiment, the targeting binding agent is administered between 6 and 12 hours prior to administration of the nanopatticles. In yet another embodiment, the targeting binding agent is administered between 2 and 8 hours prior to administration of the nanoparticles. In still other embodiments, the targeting binding agent is administered a week prior to administration of the nanoparticles. For example, administration of a dose of BEV 24 hours prior to administration of nanopa.rticle complexes comprising bevacizumab or other VEGF-binding antibody. In another example, prior administration of rituximab prior to administering rituximab-containing nanoparticle complexes. The binding agent administered prior to the nanoparticle may be administered as a dose that is subtherapeutic, such as ½, 1/10th or 1/20 the amount normally considered therapeutic. Thus, in humans, pretreatment with BEV may comprise administration of ling/kg BEV which is 1/10 th the usual dose, followed by administration of the nanoparticles or nanoparticle complexes. 
     EXAMPLES 
     The present disclosure is illustrated using nanoparticles composed of albumin-bound paclitaxel or paclitaxel derivative as a core, and bevacizumab (i.e., Avastin®) or Rituximab (i.e., Rituxang) as antibodies. 
     One skilled in the art would understand that making and using the nanoparticles of the Examples are for the sole purpose of illustration, and that the present disclosure is not limited by this illustration. 
     Any abbreviation used herein, has normal scientific meaning. All temperatures are ° C. unless otherwise stated. Herein, the following terms have the following meanings unless otherwise defined: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 ABX = 
                 ABRAXANE ®/(albumin-bound paclitaxel 
               
               
                   
                 ADC = 
                 antibody dependent chemotherapy 
               
               
                   
                 BEV = 
                 bevacizumab 
               
               
                   
                 BSA = 
                 bovine serum albumin 
               
               
                   
                 nM = 
                 nanomolar 
               
               
                   
                 FITC = 
                 Fluorescein 
               
               
                   
                 Kd = 
                 dissociation constant 
               
               
                   
                 kg = 
                 kilogram 
               
               
                   
                 M = 
                 molar 
               
               
                   
                 rug = 
                 milligram 
               
               
                   
                 ml or mL = 
                 milliliter 
               
               
                   
                 m 2  = 
                 square meters 
               
               
                   
                 mm 3  = 
                 cubic millimeter 
               
               
                   
                 μg = 
                 microgram 
               
               
                   
                 μl = 
                 microliter 
               
               
                   
                 μm = 
                 micrometer/micron 
               
               
                   
                 PBS = 
                 Phosphate buffered saline 
               
               
                   
                 RT = 
                 room temperate 
               
               
                   
                 rpm = 
                 rotations per minute 
               
               
                   
                   
               
            
           
         
       
     
     Example 1: Nanoparticle Preparation 
     Paclitaxel was reacted with Meerwein&#39;s Reagent breaking according to die reaction scheme laid out by Samaranayake et al. in “Modified Taxols. Reaction of Taxol with Electrophilic Reagents and Preperation of a Rearranged Taxol Derivative with Tubulin Assembly Activity” ( J. Org. Chem,  1991, 56, 5114-5119), which is incorporated herein by reference in its entirety. This reaction breaks the C-4,C-5 oxetane ring severely inhibiting toxicity. The reaction and purification were performed by Organix Inc. (Woburn, Mass.). The reaction is shown in  FIG. 1 . 
     The Meerwein&#39;s Product of Paclitaxel (20-Acetoxy-4-deactyl-5-epi-20, O-secotaxol) was then homogenized under high pressure with albumin to form stable non-toxic nanoparticles (NTP). Methods for homogenizing albumin and taxane (e.g., paclitaxel) can be found, for example, in U.S. Pat. Nos. 5,916,596; 6,506,405; and 6,537,579, each of which is incorporated herein by reference in its entirety. 
     Briefly, human serum albumin (HSA; Sigma Aldrich) was dissolved in sterile water at 1-1.5% w/v. In a separate container, 20-Acetoxy-4-deactyl-5-epi-20, O-secotaxol (10% w/w to HSA) was dissolved in chloroform to 10 mg/ml. Chloroform solution was added to the albumin solution and mixed with a hand-held homogenizer for 5 minutes at low RPM. The solution was run through micro-homogenizing pump at 20,000 PSI for 15 cycles. Pump coiled pathway and collection tube were placed in an ice bath to prevent solution from reaching dangerously high temps (i.e. over 50° C.). The solution was transferred to a rotary evaporator with a cold trap and run at reduced pressure for 45 minutes to evaporate off chloroform. The solution was filtered through 200 nm cellulose acetate filter. 
     For lyophilized nanoparticles, the solution was split into freeze drying flasks at appropriate volumes to allow full lyophilization of product. Flask with solution were placed. at −80° C. for 2-4 hours. The frozen solution in the flasks were lyophilized using a bench top freeze dryer with condenser of −85° C. at &lt;20 mtorr. 
     Example 2: Binding of NTP and Bevacizumab In Vitro 
     To determine whether NTP and bevacizumba (BEV) interact, the size of the NTP formed in Example 1 was analyzed by Malvern Nanosight technology, alone and after incubatluon with 4, 6, 8, and 10 miligrams per milliliter (mg/mL) of bevacizumab for 30 minutes. 
     Increasing nanoparticle diameter with increased concentration of BEV ( FIGS. 2A-2E ) suggests increased non-covalent coating of NTP with BEV. Diameter was measured at a 1:300 dilution using Malvern Nanosight technology. 
     Example 3: Affinity of Bevacizumab and Rituximab Binding to Non-Toxic Nanoparticles (NTP) 
     Binding affinity (K d ) of both bevacizumab ( FIG. 3A ) and rituximab ( FIG. 3B ) to NTP was measured using Bio Layer Interferometry Technology. Both antibodies were biotinylated using amine coupling and then bound individually to a BLITZ Streptavidin probe at 100 μg/mL. NTP at various concentrations was assayed for binding against the probe with association and dissociation periods of 120 seconds. Kinetic analysis was performed by BLITZ Evaluation software. Nano-picomolar affinities indicate strong binding between rituximab and NTP, and bevaciuzmab and NTP. 
     Example 4: Stability of Non-Toxic Nanoparticles (NTP) in PBS and Serum Compared to ABRAXANE® (ABX) 
     Antibody free NTP and ABRAXANTA (ABX) solutions were made to 30 ng/nil. of Meerwein&#39;s Product of Paclitaxel and paclitaxel, respectively, in PBS, A baseline count of nanoparticles per mL was obtained using Malvern Nanosight technology. Then a range of dilutions was made for both solutions, and particle concentration was measured. 
       FIG. 4A  shows the stability of ABX and NTP in saline. Abraxane nanoparticles began to fall apart around 1:1.33 dilution of initial solution until it reached the baseline PBS levels at ˜1:2 dilution. NTP decreased linearly with dilution factor, suggesting no particle fall apart. 
       FIG. 4B  shows the stability of ABX and NTP in serum. NTP and ABX solutions were made to 250 μg/mL of Meerwein&#39;s Product of Paclitaxel and paclitaxel, respectively, in serum. Initial concentrations of nanoparticles were measured using Malvern Nanosight Technology, subsequent measurements are presented as a percentage of initial concentration. Concentrations of each solution were measured after 15, 30, 45, and 60 minutes in smut. 
     Example 5: Daudi Cell CD20 Blocking by NTP-Ritoximab Complexes 
     ABX, AR160, Non-toxic nanoparticle (NTP) and rituximab-bound NTP were prepared as described above or previously (see, e.g., PCT Pub. No. WO2014/055415, which is incorporated herein by reference in its entirety). The nanoparticles and unlabeled rituximab were co-incubated with CD20+ Daudi lymphoma cells for 30 minutes at room temperature. The cells were washed and subsequently stained with PE anti-human CD20. Isotype ( FIG. 5A ) and anti-CD20 ( FIG. 5B ) stained cells served as negative and positive controls, respectively. 
     The results indicate the AR160 ( FIG. 5D ), rituximab loaded NT particles (NTRit;  FIG. 5F ), and rituximab ( FIG. 5G ) block subsequent binding of PE anti-human CD20, while ABX ( FIG. 5C ) and the NT nanoparticle ( FIG. 5E ) alone do not. This shows that the the rituximab in the context of AR160 and rituximab-loaded NT particles retains its ligand binding properties. 
     Example 6: Albumin-Paclitaxel Nanoparticles with Reduced Paclitaxel 
     Albumin-paclitaxel nanoparticles having reduced amounts of paclitaxel compared to ABRAXANE® are formed. 
     For example, less than 30 mg (e.g., 1 mg to 25 mg) paclitaxel is dissolved in a solvent (e.g., methylene chloride; or chloroform and ethanol). The solution is added to 27.0 mL of human serum abumin solution (1% w/v). The mixture is homogenized for 5 minutes at low RPM in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification is performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles. The resulting system is transferred into a rotary evaporator, and methylene chloride is rapidly removed at 40° C., at reduced pressure (30 mm Hg), for 20-30 minutes. Optionally, the dispersion is filtered through a 0.22 micron filter. 
     The filtered nanoparticles may be lyophilized and stored. 
     Example 7: Albumin-Paclitaxel-Therapeutic Agent Nanoparticles with Reduced Paclitaxel 
     Albumin-paclitaxel-therapeutic agent nanoparticles having reduced amounts of paclitaxel compared to ABRAXANE® are formed. 
     For example, albumin-paclitaxel nanoparticles are formed as described in Example 6. A therapeutic agent (e.g., cisplatin) is incubated with the nanoparticles at a ratio of about 10:1 (nanoparticles:agent) at room temperature for 30 min. Free therapeutic agent (e.g., cisplatin) is measured by HPLC in the supernatant after nanoparticle particulate is removed. 
     Example 8: Albumin-Paclitaxel-Antibody Nanoparticles with Reduced Paclitaxel 
     Albumin-paclitaxel-antbody nanoparticles having reduced amounts of paclitaxel compared to ABRAXANE® are formed. 
     For example, albumin-paclitaxel nanoparticles are formed as described in Example 6. Nanoparticles (10 mg) are combined with an antibody (e.g., bevacizumab) (4 mg), and 840 μl of 0.9% saline is added to give a final concentration of 10 mg/ml and 2 mg/ml of nanoparticles and antibody, respectively. The mixture is incubated for 30 minutes at room temperature to allow particle formation. 
     An antibody-albumin-paclitaxel-therapeutic agent nanoparticle complex may be formed. Optionally, antibody is incubated with albumin-paclitaxel-therapeutic agent nanoparticles (from Example 7) to form antibody-albumin-paclitaxel-therapeutic agent nanoparticle complexes. Alternatively, the antibody-albumin-paclitaxel nanoparticles my beincubated with the therapeutic agent to form antibody-albumin-paclitaxel-therapeutic agent nanoparticle complexes.